AU2015226250B2

AU2015226250B2 - 1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one derivatives and their use as antibacterial agents

Info

Publication number: AU2015226250B2
Application number: AU2015226250A
Authority: AU
Inventors: Gaelle CHAPOUX; Jean-Christophe Gauvin; Azely MIRRE; Philippe Panchaud; Christine Schmitt; Jean-Luc Specklin; Jean-Philippe Surivet
Original assignee: Idorsia Pharmaceuticals Ltd
Current assignee: Idorsia Pharmaceuticals Ltd
Priority date: 2014-03-04
Filing date: 2015-03-03
Publication date: 2018-12-13
Anticipated expiration: 2035-03-03
Also published as: JP6516370B2; PT3114126T; CL2016002207A1; BR112016020278A2; US10106544B2; PL3114126T3; TW201542556A; LT3114126T; SA516371717B1; MA39707A; WO2015132228A1; BR112016020278A8; AR099612A1; PH12016501699A1; CA2938383A1; CN106061977A; SI3114126T1; MX2016011380A; EA030708B1; TR201900393T4

Abstract

The invention relates to antibacterial compounds of formula (I), wherein R

Description

The present disclosure concerns antibacterial l,2-dihydro-37/-pyrrolo[l,2-c]imidazol-3-one derivatives, pharmaceutical compositions containing them and uses of these compounds in the manufacture of medicaments for the treatment of bacterial infections. These compounds are useful antimicrobial agents effective against a variety of human and veterinary pathogens, especially Gram-negative aerobic and anaerobic bacteria. The compounds of the present disclosure can optionally be employed in combination, either sequentially or simultaneously, with one or more therapeutic agents effective against bacterial infections.

The intensive use of antibiotics has exerted a selective evolutionary pressure on microorganisms to produce genetically based resistance mechanisms. Modem medicine and socio-economic behaviour exacerbate the problem of resistance development by creating slow growth situations for pathogenic microbes, e.g. in artificial joints, and by supporting long-term host reservoirs, e.g. in immune-compromised patients.

In hospital settings, an increasing number of strains of Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus spp., Enterobacteriaceae such as Klebsiella pneumonia, Acinetobacter baumannii and Pseudomonas aeruginosa, major sources of infections, are becoming multi-drug resistant and therefore difficult if not impossible to treat. This is particularly the case for Gram-negative organisms where the situation is getting worrisome since no novel agents have been approved for decades and the development pipeline looks empty.

Therefore, there is an important medical need for new antibacterial compounds addressing Gram-negative resistant bacteria, in particular third generation cephalosporins- and carbapenem- resistant Klebsiella pneumoniae and multi-drug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii. One way to tackle the problem of cross resistance to established classes of antibiotics is to inhibit a new target. In this respect, LpxC, which is an essential enzyme in the biosynthesis of lipopolysaccharides (a major constituent of the outer membrane of Gram-negative bacteria), has received some attention and several patent applications relating to LpxC inhibitors have been published recently.

-22015226250 05 Nov 2018

For example, WO 2011/045703 describes antibacterial compounds of formula (Al)

O (Al) wherein R¹ is (Ci-C3)alkyl; R² is H or (Ci-C3)alkyl; X is CH2, Ο, NH, S or SO2; A is an optionally substituted phenyl or a 6-membered heteroaryl group; F is absent or is S, SH, OH, -(CH₂)p-O-(CH₂)n-, -(CH₂)p-O-(CH2)z-O-(CH₂)n-, -S-(CH₂)_Z- or -(CH₂)_Z-S-; D is 5 absent or is an optionally substituted group containing a carbocyclic or heterocyclic component with optionally a (Ci-C3)alkyl chain appended; T is absent or is -(CH₂)z-, -(CH₂)_z-O- or -O-(CH2)_P-C(O)-(CH2)_n-; G is absent or is an optionally substituted carbocyclic or heterocyclic group; and n and p are integers each ranging from 0 to 3 and z is an integer ranging from 1 to 3.

WO 2011/073845 and WO 2012/120397 describe antibacterial compounds with a structural formula similar to formula (Al), whereby the group corresponding to the group A of formula (Al) however respectively represents a pyridin-2-one or a fluoropyridin-2-one residue.

WO 2012/137094 describes antibacterial compounds of formulae (A2) and (A3)

(A2) (A3) wherein R¹ is (Ci-C3)alkyl; R² is H or (Ci-C3)alkyl; R³ is H, (Ci-C3)alkoxy, (Ci-C3)alkyl, cyano, (Ci-C3)haloalkoxy, (Ci-C3)haloalkyl, halogen or hydroxy; F is a bond, -(CH2)n-, -(CH2)nO(CH2)P-, -(CH2)nNR⁴(CH2)_P-, -(CH₂)nSO2NR⁴(CH2)P-, -(CH2)nCO NR⁴(CH2)P- or -(CH2)_nNR⁴CO(CH2)_P-; R⁴ and R⁵ are independently H, (Ci-C6)alkyl, (Ci-C6)alkylcarbonyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(Ci-C6)alkyl or formyl; n is 0,

2015226250 05 Nov 2018

1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; R⁶ is (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl, (Ci-C6)alkyl-NR⁴-(Ci-C6)alkyl, (Ci-C6)alkylthio(Ci-C6)alkyl, (Ci-C6)alkylthiocarbonyl, (C6-Ci2)aryl, (C6-Ci2)aryloxy, (C6-Ci2)arylthio, (C6-Ci2)aryl-NR⁴-, (C3-Cs)cycloalkyl, (C3-Cg)cycloalkyloxy, (C3-C8)cycloalkylthio, (Cs-Csjcycloalkyl-NR⁴-, (Cs-Cnjheteroaryl, (C5-Ci2)heteroaryloxy, (Cs-Cnjheteroarylthio, (Cs-Cnjheteroaryl-NR⁴-, (C3-Ci3)heterocyclyl, (C3-Ci3)heterocyclyloxy, (C3-Ci3)heterocyclylthio, (C3-Ci3)heterocycle-NR⁴-, hydroxy(Ci-Cio)alkyl, mercapto(Ci-C6)alkyl, (NR⁴R⁵)alkyl, or (NR⁴R⁵)carbonyl; and R⁷ is absent or is (C6-Ci₂)aryl, (C6-Ci₂)aryl(Ci-C6)alkyl, (C3-Cs)cycloalkyl, (C3-C8)cycloalkyl(Ci-C6)alkyl, (Cs-Cnjheteroaryl, (C5-Ci₂)heteroaryl(Ci-C6)alkyl, (C3-Ci3)heterocyclyl or (C3-Ci3)heterocyclyl(Ci-C6)alkyl.

WO 2012/137099 describes antibacterial compounds of formula (A4)

(A4) wherein R¹ is (Ci-C3)alkyl; R² is H or (Ci-C3)alkyl; R³ is H or (Ci-C3)alkyl; X is N or CR⁴; Y is N or CR⁴; R⁴ is H or (Ci-C3)alkyl; L is a bond, (C₂-C6)alkenylene, (Ci-C6)alkylene, (C₂-C6)alkynylene, -(CH₂)nO(CH₂)_P-, -(CH₂)nS(CH₂)_P-,

-(CH₂)_nNR⁵(CH2)p-, -(CH2)nSO2NR⁵(CH2)_p-, -(CH₂)nNR⁵SO₂(CH₂)_P-,

-(CH₂)_nCONR⁵(CH2)P- or -(CH2)nNR⁵CO(CH2)_P-; R⁵ and R⁶ are independently H, (Ci-C6)alkyl, (Ci-C6)alkylcarbonyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(Ci-C6)alkyl or formyl; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; R⁷ is (C2-C6)alkenyl, (Ci-C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl, (Ci-C6)alkyl, (Ci-C6)alkylcarbonyl, (Ci-C6)alkyl-NR⁵-(Ci-C6)alkyl, (Ci-C6)alkylthio, (Ci-C6)alkylthio(Ci-C₆)alkyl, (Ci-C6)alkylthiocarbonyl, (C₂-C6)alkynyl, (C6-Ci₂)aryl, (C6-Ci₂)aryloxy, (C6-Ci₂)arylthio, (C6-Ci₂)aryl-NR⁵-, cyano, cyano(Ci-C6)alkyl, (Cs-Csjcycloalkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyloxy, (C3-C8)cycloalkylthio, (Cs-Csjcycloalkyl-NR⁵- (Cs-Cnjheteroaryl, (C5-Ci₂)heteroaryloxy, (Cs-Cnjheteroarylthio, (Cs-Cnjheteroaryl-NR⁵-, (C3-Ci3)heterocyclyl, (C3-Ci3)heterocyclyloxy, (C3-Ci3)heterocyclylthio, (C3-Ci3)heterocyclyl-NR⁵-, hydroxy(Ci-Cio)alkyl, mercapto(Ci-C6)alkyl, (NR⁵R⁶)alkyl, or

-42015226250 05 Nov 2018 (NR⁵R⁶)carbonyl; and R⁸ is absent or is (C6-Ci2)aryl, (C6-Ci2)aryl(Ci-C6)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(Ci-C6)alkyl, (Cs-Cnjheteroaryl, (C5-Ci₂)heteroaryl(Ci-C6)alkyl, (C3-Ci3)heterocyclyl or (C3-Ci3)heterocyclyl(Ci-C6)alkyl.

WO 2013/170165 describes notably antibacterial compounds of formula (A5)

O (A5) wherein A is a substituted alkyl group, wherein at least one substituent is hydroxy, or A is a substituted cycloalkyl group, wherein at least one substituent is hydroxy or hydroxyalkyl; G is a group comprising at least one carbon-carbon double or triple bond and/or a phenyl ring; D represents a group selected from

Q is O or NR, wherein R is H or an unsubstituted (Ci-C3)alkyl; R¹ and R² independently are selected from the group consisting of H and substituted or unsubstituted (Ci-C3)alkyl, or R¹ and R², together with the carbon atom to which they are attached, form an unsubstituted (C3-C4)cycloalkyl group or an unsubstituted 4-6 membered heterocyclic group; and R³ is selected from the group consisting of hydrogen, substituted or unsubstituted (Ci-C3)alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl.

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In a previous, yet unpublished patent application, we have reported antibacterial 2//-indazole derivatives of general formula (A6)

wherein

R¹ is H or halogen; R² is (CJ-Cfialkynyloxy or the group M; R³ is H or halogen; M is one of the groups M^A and M^B represented below

M^B wherein A is a bond, CH2CH2, CH=CH or C=C; R^1A represents H or halogen; R^2Arepresents H, alkoxy or halogen; R^3A represents H, alkoxy, hydroxyalkoxy, thioalkoxy, trifluoromethoxy, amino, dialkylamino, hydroxyalkyl, 1-hydroxymethyl-cycloprop-l-yl, /rans-2-hydroxymethyl-cycloprop-l-yl, 1,2-dihydroxyethyl, 3-hydroxyoxetan-3-yl,

3-(hydroxyalkyl)oxetan-3-yl, 3-aminooxetan-3-yl, 3-(dialkylamino)oxetan-3-yl,

3-hydroxythietan-3-yl, morpholin-4-ylalkoxy, morpholin-4-ylalkyl, oxazol-2-yl or [l,2,3]triazol-2-yl; and R^1B represents 3-hydroxyoxetan-3-yl, 3-hydroxythietan-3-yl, hydroxyalkyl, aminoalkyl, irans-2-hydroxymethyl-cycloprop-l-yl or 4-hydroxytetrahydro2//-pyran-4-yl.

2015226250 05 Nov 2018

In another previous, yet unpublished patent application, we have reported antibacterial

177-indazole derivatives of general formula (A7)

wherein

X represents N or CH;

R¹ represents H or halogen;

R² represents (C3-C4)alkynyloxy or the group M;

R³ represents H or halogen;

M is one of the groups M^A and M^B represented below

M^B wherein A represents a bond, CH2CH2, CH=CH or C=C;

R^1A represents H or halogen;

R^2A represents H, (Ci-C3)alkoxy or halogen;

R^3A represents H, (Ci-C3)alkoxy, hydroxy(Ci-C4)alkoxy, (Ci-C3)thioalkoxy, trifluoromethoxy, amino, hydroxy(Ci-C4)alkyl, 2-hydroxyacetamido, 1 -hydroxymethylcycloprop-1 -yl, irans-2-hydroxymethyl-cycloprop-1 -yl, 1,2-dihydroxyethyl,

3-hydroxyoxetan-3-yl, 3-(hydroxy(Ci-C3)alkyl)oxetan-3-yl, 3-aminooxetan-3-yl,

3-hydroxythietan-3-yl, morpholin-4-yl(C2-C3)alkoxy, morpholin-4-yl-(Ci-C2)alkyl, oxazol-

2-yl or [l,2,3]triazol-2-yl; and

2015226250 05 Nov 2018

R^1B represents 3-hydroxyoxetan-3-yl, 3-hydroxythietan-3-yl, hydroxy(Ci-C3)alkyl, amino(Ci-C3)alkyl, 1-hydroxymethyl-cycloprop-l-yl or /ra/7.s-2-hydroxymethyl-cycloprop-

1-yl.

Besides, in Montgomery et al., J. Med. Chem. (2012), 55(4), 1662-1670, further LpxC inhibitors are disclosed, among others the compounds of general formula (A8)

(A8) wherein R can notably be phenylethynyl or styryl, and the compound of formula (A9)

(A9)

The instant disclosure describess new antibacterial l,2-dihydro-37f-pyrrolo[l,2-c]imidazol-

3-one derivatives, namely the compounds of formula I described herein.

The term “comprising” as used in this specification and claims means “consisting at least in part of’. When interpreting statements in this specification and claims which include the term “comprising”, other features besides the features prefaced by this term in each statement can also be present. Related terms such as “comprise” and “comprised” are to be interpreted in similar manner.

In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise,

2015226250 05 Nov 2018 reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.

The invention is defined in the claims. However, the disclosure preceding the claims may refer to additional methods and other subject matter outside the scope of the present claims. This disclosure is retained for technical purposes.

In a first aspect, the invention provides a compound of formula I

I wherein

R¹ represents the group M;

M is one of the groups M^A, M^B and M^c represented below

-92015226250 05 Nov 2018

wherein A represents a bond, CH=CH or OC;

U represents N or CH;

V represents N or CH;

W represents N or CH;

R^1A represents H or halogen;

R^2A represents H, (Ci-C3)alkoxy or halogen;

R^3A represents H, halogen, (Ci-C3)alkoxy, hydroxy(C2-C4)alkoxy, dihydroxy(C3-C4)alkoxy, (C1 -C3)alkoxy(C 1 -C3)alkoxy, (C1 -C3)thioalkoxy, trifluoromethoxy, trifluoromethyl, amino, hydroxy(Ci-C4)alkyl, 1,2-dihydroxyethyl,

1-hydroxy-2,2-difluoroethyl, (Ci-C3)alkoxy(Ci-C4)alkyl, 2-hydroxy-l-oxoethyl, [(C i -C4)alkoxy] carbonyl, methylsulfonamidomethyl, 3 -hydroxy-3-methylbut-1 -yn-1 -yl,

2- hydroxyacetamido, (carbamoyloxy)methyl, 1-aminocyclopropyl, 1-hydroxymethylcycloprop-1 -yl, 1 -(((dimethylglycyl)oxy)methyl)cyclopropyl, 1 -aminomethyl-cycloprop-

-yl, 1 -(carbamoyloxy)methyl-cycloprop-1 -yl, 1 -(morpholin-4-yl)methylcycloprop-1 -yl, irans-2-hydroxymethyl-cycloprop-1 -yl, 1 -(hydroxymethyl)-cyclobut-1 -yl, l-(2-hydroxyacetyl)azetidin-3-yl, (l-ieri-butyloxycarbonyl)-3-hydroxyazetidin-3-yl,

3- hydroxyoxetan-3-yl, 3-(hydroxy(Ci-C3)alkyl)oxetan-3-yl, 3-aminooxetan-3-yl,

3-hydroxythietan-3-yl, 4-aminopiperidin-l-yl, morpholin-4-yl(C₂-C3)alkoxy, [4-7V-(Ci-C3)alkylpiperazin-l-yl](Ci-C3)alkyl, morpholin-4-yl-(Ci-C2)alkyl, [l,2,3]triazol20 2-yl, 3-[hydroxy(C2-C3)alkyl]-2-oxo-imidazolidin-l-yl, (Is,3/)-(1 -hydroxy- 102015226250 03 Dec 2018

3-(hydroxymethyl)cyclobutyl)methyl, (4-hydroxypiperidinyl)methyl or (4-aminopiperidinyl)methyl;

R^1B represents 3-hydroxyoxetan-3-yl, 3-hydroxythietan-3-yl,

3-(hydroxy(Ci-C3)alkyl)oxetan-3-yl, hydroxy(Ci-C3)alkyl, 1,2-dihydroxyethyl, amino(Ci-C3)alkyl, (dimethylamino)methyl, methylsulfonamidomethyl,

-aminocyclopropyl, 1 -hydroxymethyl-cycloprop-1 -yl, 1 -(carbamoyloxy )methylcycloprop-1 -yl, 1 -(((dimethylglycyl)oxy)methyl)cycloprop-1 -yl,

-((phosphonooxy)methyl)-cycloprop-1 -yl,

-((((phosphonooxy)methoxy)carbonyl)oxymethyl)cycloprop-1 -yl,

1 -((((phosphonooxy)methoxy)carbonyl)amino)-cycloprop-1 -yl, 7ra/7.s-2-hydroxymcthyl cycloprop-1 -yl, 1 -fluoro-2 -hydroxymethyl-cycloprop-1 -yl, 2-fluoro-2 -hydroxymethylcycloprop- 1 -yl, 1 -methyl-2-hydroxymethyl-cycloprop-1 -yl, 2-hydroxymethyl-

2-methylcycloprop-l-yl, (lR*,2₁S^,*,35*)-l,2-Z>z5-(hydroxymethyl)-cycloprop-3-yl,

1- (hydroxymethyl)cyclobut-l-yl, 3-amino-oxetan-3-yl, 3-(hydroxy(Ci-C3)alkyl)oxetan-

3-yl, l-(2-hydroxyacetyl)-azetidin-3-yl, /ra/7.s-(c/.s-3,4-dihydroxy)-cyclopcnt-l-yl,

-hydroxymethyl-bicyclo[ 1,1,1 Jpcntan-1 -yl, 4-hydroxy-tetrahyd ro-2//-pyran-4-yl,

5-amino-tctrahydiO-2//-pyran-2-yl, 3-hydroxyoxetan-3-ylmethyl, 1-cyclobutyl-

2- hydroxyethyl or l-(oxetan-3-yl)-azetidin-3-yl; and

R^1C represents 1-aminocyclopropyl or hydroxy(Ci-C3)alkyl;

or a salt of this compound.

In a further aspect, the invention provides a method of treating a patient with a Gramnegative bacterial infection comprising administering to the patient an effective amount of a compound of formula I as defined the first aspect.

In a further aspect, the invention provides a pharmaceutical composition containing, as active ingredient, a compound of formula I as defined in the first aspect, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.

In a further aspect, the invention provides a compound of formula I as defined in the first aspect, or a pharmaceutically acceptable salt thereof, when used for the prevention or treatment of a Gram-negative bacterial infection.

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In a further aspect, the invention provides the use of a compound of formula I as defined in the first aspect, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a Gram-negative bacterial infection.

Various disclosures are presented hereafter:

1) The disclosure relates to compounds of formula I

I wherein

R¹ represents the group M;

M is one of the groups M^A, M^B and M^c represented below

wherein A represents a bond, CH=CH or C=C;

U represents N or CH;

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V represents N or CH;

W represents N or CH;

R^1A represents H or halogen;

R^2A represents H, (Ci-C3)alkoxy or halogen;

R^3A represents H, halogen, (Ci-C3)alkoxy, hydroxy(C2-C4)alkoxy, dihydroxy(C3-C4)alkoxy, (C1-C3 )alkoxy(C 1-C3 )alkoxy, (C1 -C3)thioalkoxy, trifluoromethoxy, trifluoromethyl, amino, hydroxy(Ci-C4)alkyl, 1,2-dihydroxyethyl, 1 -hydroxy-2,2-difluoroethyl, (Ci-C3)alkoxy(Ci-C4)alkyl, 2-hydroxy-l-oxoethyl, [(C1 -C4)alkoxy] carbonyl, methylsulfonamidomethyl, 3 -hydroxy-3-methylbut-1 -yn-1 -yl, 10 2-hydroxyacetamido, (carbamoyloxy)methyl, 1-aminocyclopropyl, 1-hydroxymethylcycloprop-1 -yl, 1 -(((dimethylglycyl)oxy)methyl)-cycloprop-1 -yl, 1 -aminomethylcycloprop-1 -yl, 1 -(carbamoyloxy)methyl-cycloprop-1 -yl, 1 -(morpholin-4-yl)methylcycloprop-1 -yl, Zrans-2-hydroxymethyl-cycloprop-1 -yl, 1 -(hydroxymethyl)-cyclobut-1 -yl,

1- (2-hydroxyacetyl)azetidin-3-yl, (l-ieri-butyloxycarbonyl)-3-hydroxyazetidin-3-yl,

3-hydroxyoxetan-3-yl, 3-(hydroxy(Ci-C3)alkyl)oxetan-3-yl, 3-aminooxetan-3-yl,

3-hydroxythietan-3-yl, 4-aminopiperidin-l-yl, morpholin-4-yl(C2-C3)alkoxy, [4-7V-(Ci-C3)alkylpiperazin-l-yl](Ci-C3)alkyl, morpholin-4-yl-(Ci-C2)alkyl, [l,2,3]triazol-

2- yl, 3-[hydroxy(C2-C3)alkyl]-2-oxo-imidazolidin-l-yl, (7s,3r)-(l-hydroxy -

3- (hydroxymethyl)cyclobutyl)methyl, (4-hydroxypiperidinyl)methyl or (4-aminopiperidinyl)methyl;

R^1B represents 3-hydroxyoxetan-3-yl, 3-hydroxythietan-3-yl,

-aminocyclopropyl, 1 -hydroxymethyl-cycloprop-1 -yl, 1 -(carbamoyloxy )methyl25 cycloprop-1 -yl, 1 -(((dimethylglycyl)oxy)methyl)-cycloprop-1 -yl,

-((phosphonooxy)methyl)-cycloprop-1 -yl,

-((((phosphonooxy)methoxy)carbonyl)oxymethyl)-cycloprop-1 -yl,

-((((phosphonooxy)methoxy)carbonyl)amino)-cycloprop-1 -yl, 7ra/7.s-2-hydroxymcthyl cycloprop-1 -yl, 1 -fluoro-2-hydroxymethyl-cycloprop-1 -yl, 2-fluoro-2-hydroxymethyl30 cycloprop-1-yl, l-methyl-2-hydroxymethyl-cycloprop-l-yl, 2-hydroxymethyl-

2- methylcycloprop-l-yl, (lR*,2S'*,3s*)-l,2-rtzs-(hydroxymethyl)-cycloprop-3-yl, l-(hydroxymethyl)cyclobut-l-yl, 3-amino-oxetan-3-yl, 3-(hydroxy(Ci-C3)alkyl)oxetan-

3- yl, l-(2-hydroxyacetyl)-azetidin-3-yl, 7ra/7.s-(c/.s-3,4-dihydiOxy)-cyclopcnt-l-yl,

- 13 2015226250 05 Nov 2018

3-hydroxymethyl-bicyclo[ 1,1,1 ]pentan-1 -yl, 4-hydroxy-tctrahydro-2//-pyran-4-yl,

5-amino-tetrahydro-2//-pyran-2-yl, 3-hydroxyoxetan-3-ylmethyl, 1-cyclobutyl-

2-hydroxyethyl or l-(oxetan-3-yl)-azetidin-3-yl; and

R^1C represents 1-aminocyclopropyl or hydroxy(Ci-C3)alkyl;

and to salts (in particular pharmaceutically acceptable salts) of compounds of formula I.

The following paragraphs provide definitions of the various chemical moieties for the compounds described herein and are intended to apply uniformly throughout the specification and claims, unless an otherwise expressly set out definition provides a broader or narrower definition:

♦♦♦ The term “alkyl”, used alone or in combination, refers to a straight or branched chain alkyl group containing from one to four carbon atoms. The term “(C_x-C_y)alkyl” (x and y each being an integer) refers to a straight or branched chain alkyl group containing x to y carbon atoms. For example, a (Ci-C3)alkyl group contains from one to three carbon atoms. Representative examples of alkyl groups include methyl, ethyl, propyl, 15 /'.so-propyl, n-butyl, iso-butyl, sec-butyl and ieri-butyl. Preferred are methyl and ethyl.

Most preferred is methyl.

❖ The term “hydroxyalkyl”, used alone or in combination, refers to an alkyl group as defined before wherein one hydrogen atom has been replaced by a hydroxy group. The term “hydroxy(C_x-C_y)alkyl” (x and y each being an integer) refers to a hydroxyalkyl 20 group as defined which contains x to y carbon atoms. For example, a hydroxyfCi-CQalkyl group is a hydroxyalkyl group as defined before which contains from one to four carbon atoms. Representative examples of hydroxyalkyl groups include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl and 3-hydroxypropyl. Preferred are hydroxymethyl and 2-hydroxyethyl. Most preferred is hydroxymethyl.

♦♦♦ The term “aminoalkyl”, used alone or in combination, refers to an alkyl group as defined before wherein one hydrogen atom has been replaced by an amino group. The term “amino(C_x-C_y)alkyl” (x and y each being an integer) refers to an aminoalkyl group as defined which contains x to y carbon atoms. For example, an aminofCi-CQalkyl group is an aminoalkyl group as defined before which contains 30 from one to four carbon atoms. Representative examples of aminoalkyl groups include aminomethyl, 2-aminoethyl, 2-aminopropyl, 2-aminoprop-2-yl and 3-aminopropyl.

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Preferred are aminomethyl, 2-aminoethyl and 2-aminopropyl. Most preferred is

2-aminoprop-2-yl.

❖ The term “alkoxy”, used alone or in combination, refers to a straight or branched chain alkoxy group containing from one to four carbon atoms. The term “(C_x-C_y)alkoxy” (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms. For example, a (Ci-C3)alkoxy group contains from one to three carbon atoms. Representative examples of alkoxy groups include methoxy, ethoxy, //-propoxy and z.so-propoxy. Preferred are methoxy and ethoxy. Most preferred is methoxy.

❖ The term “hydroxyalkoxy”, used alone or in combination, refers to a straight or branched chain alkoxy group containing from one to four carbon atoms wherein one of the carbon atoms bears a hydroxy group. The term “hydroxy(C_x-C_y)alkoxy” (x and y each being an integer) refers to a hydroxyalkoxy group as defined before containing x to y carbon atoms. For example, a hydroxy(C2-C4)alkoxy group contains from two to four carbon atoms. Representative examples of hydroxyalkoxy groups include 15 2-hydroxyethoxy, 2-hydroxypropoxy, 3-hydroxypropoxy and 4-hydroxybutoxy.

Preferred are 2-hydroxyethoxy and 3-hydroxypropoxy. Most preferred is

2-hydroxyethoxy.

❖ The term “dihydroxyalkoxy”, used alone or in combination, refers to an alkoxy group containing from three to four carbon atoms wherein two hydrogen atoms on two different carbon atoms have each been replaced by a hydroxy group. For example “dihydroxy(C3-C4)alkoxy” refers to an alkoxy group containing from three to four carbon atoms wherein two hydrogen atoms on two different carbon atoms have each been replaced by a hydroxy group. A preferred dihydroxy(C3-C4)alkoxy group is 2,3 -dihydroxypropoxy.

♦♦♦ The term “thioalkoxy”, used alone or in combination, refers to a straight or branched chain alkoxy group containing from one to four carbon atoms wherein the oxygen atom has been replaced by a sulphur atom. The term “(C_x-C_y)thioalkoxy” (x and y each being an integer) refers to a thioalkoxy group as defined before containing x to y carbon atoms. For example, a (Ci-C3)thioalkoxy group contains from one to three 30 carbon atoms. Representative examples of thioalkoxy groups include methylthio, ethylthio, n-propylthio and z.so-propylthio. Preferred are methylthio and ethylthio. Most preferred is methylthio.

- 15 2015226250 05 Nov 2018 ❖ The term “3-(hydroxy(Ci-C3)alkyl)oxetan-3-yl” refers to an oxetan-3-yl group wherein the hydrogen on the carbon at position 3 of the oxetane ring has been replaced by a hydroxy(Ci-C3)alkyl group as defined before. Examples of

3-(hydroxy(Ci-C3)alkyl)oxetan-3-yl groups are 3-hydroxymethyl-oxetan-3-yl and

3-(2-hydroxyethyl)-oxetan-3-yl. The most preferred 3-(hydroxy(Ci-C3)alkyl)oxetan-

3-yl group is 3-hydroxymethyl-oxetan-3-yl.

❖ The term “morpholin-4-yl-(Ci-C2)alkyl” refers to a (Ci-C2)alkyl group as defined before wherein one of the hydrogen atoms has been replaced by a morpholin-4-yl group. Examples of morpholin-4-yl-(Ci-C2)alkyl groups are morpholin-4-ylmethyl and

2-morpholin-4-yl-ethyl. The most preferred morpholino(Ci-C2)alkyl group is morpholin-4-ylmethyl.

❖ The term “halogen” refers to fluorine, chlorine, bromine or iodine, and preferably to fluorine or chlorine, and most preferably to fluorine.

❖ The term “quinolone-resistant”, when used in this text, refers to a bacterial strain against which ciprofloxacin has a Minimal Inhibitory Concentration of at least 16 mg/1 (said Minimal Inhibitory Concentration being measured with the standard method described in “Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically”, Approved standard, 7^th ed., Clinical and Laboratory Standards Institute (CLSI) Document M7-A7, Wayne, PA, USA (2006)).

♦♦♦ The term “multi-drug resistant”, when used in this text, refers to a bacterial strain against which at least three antibiotic compounds selected from three distinct antibiotic categories have Minimal Inhibitory Concentrations (MICs) over their respective clinical breakpoints, whereby said three distinct antibiotic categories are chosen among penicillins, combinations of penicillins with beta-lactamase inhibitors, cephalosporins, carbapenems, monobactams, fluoro-quinolones, aminoglycosides, phosphonic acids, tetracyclins and polymixins. Clinical breakpoints are defined according to the latest available list published by Clinical and Laboratory Standards Institute (Wayne, PA, USA). Accordingly, clinical breakpoints are the levels of MIC at which, at a given time, a bacterium is deemed either susceptible or resistant to treatment by the corresponding antibiotic or antibiotic combination.

- 162015226250 05 Nov 2018

The term pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound. For reference see 5 for example Handbook of Pharmaceutical Salts. Properties, Selection and Use.’, P.

Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH (2008) and Pharmaceutical Salts and Co-crystals’’, Johan Wouters and Luc Quere (Eds.), RSC Publishing (2012).

In this text, a bond interrupted by a wavy line shows a point of attachment of the radical drawn to the rest of the molecule. For example, the radical drawn below

wherein A represents a bond, and each of R^1A, R^2A and R^3A represents H is the phenyl group.

Besides, the term “room temperature” as used herein refers to a temperature of 25°C.

Unless used regarding temperatures, the term “about” placed before a numerical value “X” refers in the current application to an interval extending from X minus 10% of X to X plus 15 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of

X. In the particular case of temperatures, the term “about” placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10°C to Y plus 10°C, and preferably to an interval extending from Y minus 5°C to Y plus 5°C.

2015226250 05 Nov 2018

2) Described herein are compounds of formula I according to disclosure 1) which are also compounds of formula Ip

wherein

R¹ represents the group M;

M is one of the groups M^A and M^B represented below _R1A

_R3A

M^A M^b wherein A represents a bond, CH=CH or C=C;

U represents N or CH;

V represents N or CH;

R^1A represents H or halogen;

R^2A represents H, (Ci-C3)alkoxy or halogen;

R^3A represents H, (Ci-C3)alkoxy, hydroxy(C2-C4)alkoxy, (Ci-C3)alkoxy(Ci-C3)alkoxy, (Ci-C3)thioalkoxy, trifluoromethoxy, amino, hydroxy(Ci-C4)alkyl, (C i -C₃)alkoxy(C i -C4)alkyl, 3 -hydroxy-3 -methylbut-1 -yn-1 -yl, 2-hydroxyacetamido, (carbamoyloxy)methyl, 1 -hydroxymethyl-cycloprop-1 -yl, 1 -aminomethyl-cycloprop-1 -yl, 15 1 -(carbamoyloxy)methyl-cycloprop-1 -yl, 1 -(morpholin-4-yl)methylcycloprop-1 -yl, irans-2-hydroxymethyl-cycloprop-l-yl, 1,2-dihydroxyethyl, 3-hydroxyoxetan-3-yl,

- 18 2015226250 05 Nov 2018

3- (hydroxy(Ci-C3)alkyl)oxetan-3-yl, 3-aminooxetan-3-yl, 3-hydroxythietan-3-yl, morpholin-4-yl(C2-C3)alkoxy, [4-7V-(C 1 -C3)alkylpiperazin-1 -yl] (C1 -C3)alkyl, morpholin-

4- yl-(Ci-C2)alkyl, [l,2,3]triazol-2-yl or 3-[hydroxy(C2-C3)alkyl]-2-oxo-imidazolidin-l-yl; and

R^1B represents 3-hydroxyoxetan-3-yl, 3-hydroxythietan-3-yl,

3-(hydroxy(Ci-C3)alkyl)oxetan-3-yl, hydroxy(Ci-C3)alkyl, 1,2-dihydroxyethyl, amino(Ci-C3)alkyl, 1-hydroxymethyl-cycloprop-l-yl, irans-2-hydroxymethyl-cycloprop-

1-yl, ira«5-(cz5-3,4-dihydroxy)-cyclopent-l-yl or 3-hydroxymethylbicyclo[1,1,1 Jpentan- i-yi;

and to salts (in particular pharmaceutically acceptable salts) of compounds of formula Ip.

3) Descirbed herein are compounds of formula I according to disclosure 1) which are also compounds of formula Ice

wherein

R¹ represents the group M;

M is one of the groups M^A, M^B and M^c represented below

- 192015226250 05 Nov 2018

wherein A represents a bond, CH=CH or C=C;

U represents CH orN;

V represents CH orN;

W represents CH orN;

R^1A represents H or halogen;

R^2A represents H, (Ci-C3)alkoxy or halogen; R^3A represents H, dihydroxy(C3-C4)alkoxy, hydroxy(C i-C4)alkyl, (Ci-C₃)alkoxy(Ci-C4)alkyl, methylsulfonamidomethyl, (carbamoyloxy)methyl, halogen, (Ci-C3)alkoxy, hydroxy(C2-C4)alkoxy, (Ci-C3)alkoxy(Ci-C3)alkoxy, trifluoromethyl,

1,2-dihydroxyethyl, 1 -hydroxy-2,2-difluoroethyl,

2-hydroxy-l-oxoethyl, [(Ci-C4)alkoxyJ carbonyl,

3-hydroxy-3 -methylbut-1 -yn-1 -yl, 2-hydroxyacetamido,

-aminocyclopropyl, 1 -hydroxymethyl-cycloprop-1 -yl,

-(((dimethylglycyl)oxy)methyl)cyclopropyl, 1 -aminomethyl-cycloprop-1 -yl,

-(carbamoyloxy)methyl-cycloprop-1 -yl, 1 -(morpholin-4-yl)methylcycloprop-1 -yl, trans-2 -hydroxymethyl-cycloprop-1 -yl, 1 -(hydroxymethyl)-cyclobut-1 -yl, l-(2-hydroxyacetyl)azetidin-3-yl, (l-ieri-butyloxycarbonyl)-3-hydroxyazetidin-3-yl,

3- hydroxyoxetan-3-yl, 3-(hydroxy(Ci-C3)alkyl)oxetan-3-yl, 3-aminooxetan-3-yl,

4- aminopiperidin-l-yl, [4-7V-(Ci-C3)alkylpiperazin-l-yl](Ci-C3)alkyl, morpholin-4-yl- (Ci-C₂)alkyl, 3-[hydroxy(C2-C3)alkyl]-2-oxo-imidazolidin-l-yl, (/s ,//·)-( I-hydroxy20 3-(hydroxymethyl)cyclobutyl)methyl, (4-hydroxypiperidinyl)methyl or (4-aminopiperidinyl)methyl;

R^1B represents 3-hydroxyoxetan-3-yl, hydroxy(Ci-C₃)alkyl, 1,2-dihydroxyethyl, amino(Ci-C3)alkyl, (dimethylamino)methyl, methylsulfonamidomethyl,

-((phosphonooxy)methyl)-cycloprop-1 -yl,

-((((phosphonooxy)methoxy)carbonyl)oxymethyl)-cycloprop-1 -yl,

-202015226250 05 Nov 2018

-((((phosphonooxy)methoxy)carbonyl)amino)-cycloprop-1 -yl, /ra/7.s-2-hydroxymcthyl cycloprop-1 -yl, 1 -fluoro-2-hydroxymethyl-cycloprop-1 -yl, 2-fluoro-2-hydroxymethylcycloprop-1 -yl, 1 -methyl-2-hydroxymethyl-cycloprop-1 -yl, 2-hydroxymethyl-

2- methylcycloprop-l-yl, (17?*,2₁S'*,35*)-l,2-0z5-(hydroxymethyl)-cycloprop-3-yl, l-(hydroxymethyl)cyclobut-l-yl, 3-amino-oxetan-3-yl, 3-(hydroxy(Ci-C3)alkyl)oxetan-

3- yl, l-(2-hydroxyacetyl)-azetidin-3-yl, /ra/7.s-(c/.s-3,4-dihydroxy)-cyclopcnt-l-yl,

3-hydroxymethylbicyclo[l,l,l]pentan-l-yl, 4-hydroxy-tctrahydro-2//-pyran-4-yl, 5-aminotetrahydro-2//-pyran-2-yl, 3-hydroxyoxetan-3-ylmethyl, l-cyclobutyl-2-hydroxyethyl or l-(oxetan-3-yl)-azetidin-3-yl; and

R^1C represents 1-aminocyclopropyl or hydroxy(Ci-C3)alkyl;

and to salts (in particular pharmaceutically acceptable salts) of compounds of formula Ice.

4) Described herein are compounds of formula I according to disclosure 3) which are also compounds of formula Icep

wherein

R¹ represents the group M;

-21 2015226250 05 Nov 2018

M is one of the groups M^A and M^B represented below

R^1A

_R3A

M^A M^B wherein A represents a bond, CH=CH or C=C;

U represents CH orN;

V represents CH orN;

R^1A represents H or halogen;

R^2A represents H, (Ci-C3)alkoxy or halogen;

R^3A represents H, (Ci-C3)alkoxy, hydroxy(C2-C4)alkoxy, (Ci-C3)alkoxy(Ci-C3)alkoxy, hydroxy(C i-C4)alkyl, (C1 -C3)alkoxy(C 1 -C4)alkyl, 3 -hydroxy-3-methylbut-1 -yn-1 -yl,

2- hydroxyacetamido, (carbamoyloxy)methyl, 1 -hydroxymethyl-cycloprop-1 -yl,

1-aminomethyl-cycloprop-l-yl, l-(carbamoyloxy)methyl-cycloprop-l-yl, 1-(morpholin-

4-yl)methylcycloprop-1 -yl, trans-1 -hydroxymethyl-cycloprop-1 -yl, 1,2-dihydroxyethyl,

3- hydroxyoxetan-3-yl, [4-A-(C i -C3)alkylpiperazin-1 -yl] (C i -C3)alkyl, morpholin-4-yl- (Ci-C2)alkyl or 3-[hydroxy(C2-C3)alkyl]-2-oxo-imidazolidin-l-yl; and

R^1B represents 3-hydroxyoxetan-3-yl, hydroxy(Ci-C3)alkyl, 1,2-dihydroxyethyl, 15 amino(Ci-C3)alkyl, 1-hydroxymethyl-cycloprop-1-yl, irans-2-hydroxymethyl-cycloprop-

1-yl, irans-(czs-3,4-dihydroxy)-cyclopent-l-yl or 3-hydroxymethylbicyclo[1,1,1 ]pentan-

1-yi;

and to salts (in particular pharmaceutically acceptable salts) of compounds of formula Icep.

-222015226250 05 Nov 2018

5) In particular, the compounds of formula Ice according to disclosure 3) or 4) will be such that R¹ represents the group M and M represents the group M^A or M^B

R^1A

_R3A

M^A M^b wherein A represents a bond, CH=CH or C=C;

U represents CH orN;

V represents CH;

R^1A represents H or fluorine;

R^2A represents H, methoxy or fluorine;

R^3A represents H, (Ci-C3)alkoxy, hydroxy(C2-C4)alkoxy, (Ci-C3)alkoxy(Ci-C3)alkoxy, hydroxy(C i-C4)alkyl, (C i -C3)alkoxy(C i -C4)alkyl, 3 -hydroxy-3-methylbut-1 -yn-1 -yl,

2-hydroxyacetamido, (carbamoyloxy)methyl, 1-hydroxymethyl-cycloprop-l-yl,

-aminomethyl-cycloprop-1 -yl, 1 -(carbamoyloxy)methyl-cycloprop-1 -yl, 1 -(morpholin-

4-yl)methylcycloprop-1 -yl, /ra/7.s-2-hydroxymethyl-cycloprop-1 -yl, 1,2-dihydroxyethyl, 3-hydroxyoxetan-3-yl, [4-7V-(C i -C3)alkylpiperazin-1 -yl] (C i -C3)alkyl, morpholin-4-yl(Ci-C2)alkyl or 3-[hydroxy(C2-C3)alkyl]-2-oxo-imidazolidin-l-yl; and

R^1B represents 3-hydroxyoxetan-3-yl, hydroxy(Ci-C3)alkyl, 1,2-dihydroxyethyl, amino(Ci-C3)alkyl, 1-hydroxymethyl-cycloprop-l-yl, irans-2-hydroxymethyl-cycloprop-

1-yl, irans-(czs-3,4-dihydroxy)-cyclopent-l-yl or 3-hydroxymethylbicyclo [1,1,1 Jpentan- i-yi;

6) According to one main disclosure, the compounds of formula I as defined in one of 20 disclosures 1) to 5) will be such that R¹ represents the group M^A.

7) One sub-disclosure of disclosure 6) relates to the compounds of formula I as defined in disclosure 6) wherein A represents a bond.

8) Preferably, the compounds of formula I according to disclosure 7) will be such that U represents CH, V represents CH, R^1A represents H or halogen, R^2A represents H or

2015226250 05 Nov 2018 (Ci-C3)alkoxy and R^3A represents H, halogen, (Ci-C3)alkoxy or 3-hydroxy-3-methylbut-

1- yn-l-yl (and in particular such that U represents CH, V represents CH, R^1A represents H or halogen, R^2A represents H or (Ci-C3)alkoxy and R^3A represents H, (Ci-C3)alkoxy or 3 -hydroxy-3 -methylbut-1 -yn-1 -yl).

9) More preferably, the compounds of formula I according to disclosure 7) will be such that U represents CH, V represents CH, R^1A represents H, chlorine or fluorine, R^2Arepresents H or methoxy and R^3A represents H, chlorine, fluorine, methoxy or 3-hydroxy3-methylbut-1-yn-l-yl (and in particular such that U represents CH, V represents CH, R^1Arepresents H or fluorine, R^2A represents H or methoxy and R^3A represents H, methoxy or 10 3 -hydroxy-3 -methylbut-1 -yn-1 -yl).

10) Another sub-disclosure of disclosure 6) relates to the compounds of formula I as defined in disclosure 6) wherein A represents C=C.

11) Preferably, the compounds of formula I according to disclosure 10) will be such that U represents CH or N, V represents CH, R^1A represents H or halogen, R^2A represents H or halogen and R^3A represents hydroxy(C2-C4)alkoxy, hydroxy(Ci-C4)alkyl,

1,2-dihydroxyethyl, l-hydroxy-2,2-difluoroethyl, methylsulfonamidomethyl, 3-hydroxy3-methylbut-1-yn-l-yl, 2-hydroxyacetamido, (carbamoyloxy)methyl, 1-aminocyclopropyl,

-hydroxymethyl-cycloprop-1 -yl, 1 -aminomethyl-cycloprop-1 -yl,

-(carbamoyloxy)methyl-cycloprop-1 -yl, 1 -(morpholin-4-yl)methylcycloprop-1 -yl, trans-2 -hydroxymethyl-cycloprop-1 -yl, 1 -(hydroxymethyl)-cyclobut-1 -yl,

3- hydroxyoxetan-3-yl, 3-(hydroxy(Ci-C3)alkyl)oxetan-3-yl, 3-aminooxetan-3-yl,

4- aminopiperidin-l-yl, [4-A-(Ci-C3)alkylpiperazin-l-yl](Ci-C3)alkyl, morpholin-4-yl- (Ci-C₂)alkyl, 3-[hydroxy(C₂-C3)alkyl]-2-oxo-imidazolidin-l-yl or (4-hydroxypiperidinyl)methyl (and in particular such that U represents CH or N, V represents CH, R^1A represents H or halogen, R^2A represents H or halogen and R^3Arepresents hydroxy(C₂-C4)alkoxy, hydroxy(Ci-C4)alkyl, 3-hydroxy-3-methylbut-l-yn-l-yl,

2- hydroxyacetamido, (carbamoyloxy)methyl, 1 -hydroxymethyl-cycloprop-1 -yl,

4-yl)methylcycloprop-1 -yl, /ra/7.s-2-hydiOxymethyl-cycloprop-1 -yl, 1,2-dihydroxyethyl, 30 3-hydroxyoxetan-3-yl, [4-A-(Ci-C3)alkylpiperazin-l-yl](Ci-C3)alkyl, morpholin-4-yl(Ci-C₂)alkyl or 3-[hydroxy(C₂-C3)alkyl]-2-oxo-imidazolidin-l-yl).

2015226250 05 Nov 2018

12) More preferably, the compounds of formula I according to disclosure 10) will be such that U represents CH, V represents CH, R^1A represents H or fluorine, R^2A represents H or fluorine and R^3A represents hydroxy(C2-C4)alkoxy, hydroxy(Ci-C4)alkyl,

1,2-dihydroxyethyl, 1 -hydroxy-2,2-difluoroethyl, methylsulfonamidomethyl,

2-hydroxyacetamido, (carbamoyloxy)methyl, 1-aminocyclopropyl, 1-hydroxymethylcycloprop-1 -yl, 1 -(carbamoyloxy)methyl-cycloprop-1 -yl, /ra/7.s-2-hydroxymethylcycloprop-l-yl, l-(hydroxymethyl)-cyclobut-l-yl, 3-hydroxyoxetan-3-yl, morpholin4-ylmethyl or (4-hydroxypiperidinyl)methyl (and in particular such that U represents CH, V represents CH, R^1A represents H or fluorine, R^2A represents H or fluorine and R^3A represents hydroxy(C₂-C4)alkoxy, hydroxy(Ci-C4)alkyl, 2-hydroxyacetamido, (carbamoyloxy)methyl, 1 -hydroxymethyl-cycloprop-1 -yl, 1 -(carbamoyloxy )methylcycloprop-1 -yl, irans-2-hydroxymethyl-cycloprop-1 -yl, 1,2-dihydroxyethyl,

3-hydroxyoxetan-3-yl or morpholin-4-ylmethyl).

13) Even more preferably, the compounds of formula I according to disclosure 10) will be such that U represents CH, V represents CH, R^1A represents H or fluorine, R^2A represents H or fluorine and R^3A represents hydroxy(C2-C4)alkoxy, hydroxy(Ci-C4)alkyl,

1.2- dihydroxyethyl, 2-hydroxyacetamido, (carbamoyloxy)methyl, 1-aminocyclopropyl,

-hydroxymethyl-cycloprop-1 -yl, 1 -(carbamoyl oxy)methyl-cycloprop-1 -yl, /rans-2-hydroxymethyl-cycloprop-l-yl or 3-hydroxyoxetan-3-yl (and in particular such that U represents CH, V represents CH, R^1A represents H or fluorine, R^2A represents H or fluorine and R^3A represents hydroxy(C2-C4)alkoxy, hydroxy(Ci-C4)alkyl,

2-hydroxyacetamido, (carbamoyloxy)methyl, 1 -hydroxymethyl-cycloprop-1 -yl,

-(carbamoyloxy)methyl-cycloprop-1 -yl, traus-l-hyA roxymet hyl-cycloprop-1 -yl,

1.2- dihydroxyethyl or 3-hydroxyoxetan-3-yl).

14) Yet another sub-disclosure of disclosure 6) relates to the compounds of formula I as defined in disclosure 6) wherein A represents CH=CH.

15) Preferably, the compounds of formula I according to disclosure 14) will be such that U represents CH, V represents CH, R^1A represents H, R^2A represents H and R^3A represents hydroxy(Ci-C4)alkyl (in particular hydroxymethyl).

16) According to another main disclosure, the compounds of formula I as defined in one of disclosures 1) to 5) will be such that R¹ represents the group M^B.

2015226250 05 Nov 2018

17) Preferably, the compounds of formula I according to disclosure 16) will be such that

R^1B represents 3-hydroxyoxetan-3-yl, hydroxy(Ci-C3)alkyl, amino(Ci-C3)alkyl,

-hydroxymethyl-cycloprop-1 -yl, 1 -(carbamoyloxy )methyl1 -((((phosphonooxy)methoxy)carbonyl)oxymethyl)-cycloprop-1 -yl,

-fluoro-2-hydroxymethyl-cycloprop-1 -yl,

-methyl-2-hydroxymethyl-cycloprop-1 -yl,

-(hydroxymethyl)cyclobut-1 -yl, irazzs-(czs-3,4-dihydroxy)-cyclopent-l-yl, 5-amino-tetrahydro-2//-pyran-2-yl or represents

-aminocyclopropyl, cycloprop-1-yl, irazzs-2-hydroxymethyl-cycloprop-1 -yl,

2-fluoro-2-hydroxymethyl-cycloprop-1 -yl,

2- hydroxymethyl-2-methylcycloprop-l-yl, l-(2-hydroxyacetyl)-azetidin-3-yl,

-hydroxymethylbicyclo [1,1,1 Jpentan-1 -yl, l-(oxetan-3-yl)-azetidin-3-yl (and in particular such that R^1B represents 3-hydroxyoxetan-

3- yl, hydroxy(Ci-C3)alkyl, amino(Ci-C3)alkyl, 1-hydroxymethyl-cycloprop-l-yl, irazzs-2-hydroxymethyl-cycloprop-1 -yl, trans-(cis-3,4-dihydroxy)-cyclopent-1 -yl or

-hydroxymethylbicyclo [1,1,1 Jpentan-1 -yl).

18) More preferably, the compounds of formula I according to disclosure 16) will be such that R^1B represents amino(Ci-C3)alkyl, 1-aminocyclopropyl, 1-hydroxymethyl-cycloprop-

-fluoro-2-hydroxymethyl-cycloprop-1 -yl, 1 -methyl-2 -hydroxymethyl-cycloprop-1 -yl, l-(2-hydroxyacetyl)-azetidin-3-yl,

3-hydroxymethylbicyclo [1,1,1 Jpentan-1 -yl,

-yl, irazzs-2-hydroxymethyl-cycloprop-1 -yl,

2-fluoro-2-hydroxymethyl-cycloprop-1 -yl,

2- hydroxymethyl-2-methylcycloprop-1 -yl, irazzs-(czs-3,4-dihydroxy)-cyclopent-l-yl,

5-amiiK)-tctrahydro-2//-pyran-2-yl or l-(oxetan-3-yl)-azetidin-3-yl (and in particular such that R^1B represents amino(Ci-C3)alkyl, 1-hydroxymethyl-cycloprop-l-yl, irazzs-2-hydroxymethyl-cycloprop-1 -yl, trans-(cis-3,4-dihydroxy)-cyclopent-1 -yl or

3- hydroxymethylbicyclo [1,1,1 Jpentan-1 -yl).

19) Even more preferably, the compounds of formula I according to disclosure 16) will be such that R^1B represents irazzs-2-hydroxymethyl-cycloprop-l-yl, 1-fluoro-

2-hydroxymethyl-cycloprop-l-yl, 2-fluoro-2-hydroxymethyl-cycloprop-l-yl,

-methyl-2-hydroxymethyl-cycloprop-1 -yl, 2-hydroxymethyl-2 -methylcycloprop-1 -yl, trans-(cis-3,4-dihydroxy)-cyclopent-1 -yl or 3-hydroxymethylbicyclo[ 1,1,1 Jpentan-1 -yl (and in particular such that R^1B represents irazzs-2-hydroxymethyl-cycloprop-l-yl, 30 Zrazzs-(czs-3,4-dihydroxy)-cyclopent-l-yl or 3-hydroxymethylbicyclo[l,l,l]pentan-l-yl).

-262015226250 05 Nov 2018

20) According to yet another main disclosure, the compounds of formula I as defined in disclosure 1) or 3) will be such that R¹ represents the group M^c.

21) According to one variant of disclosure 20), the compounds of formula I as defined in disclosure 1) or 3) will be such that W represents CH.

22) Preferably, the compounds of formula I according to disclosure 21) will be such that

R^1C represents 1-aminocyclopropyl.

23) According to the other variant of disclosure 20), the compounds of formula I as defined in disclosure 1) or 3) will be such that W represents N.

24) Preferably, the compounds of formula I according to disclosure 23) will be such that

R^1C represents hydroxy(Ci-C3)alkyl (and in particular 2-hydroxypropan-2-yl).

25) In a preferred disclosure, the compounds of formula I according to disclosure 1) or 3) will be such that R¹ represents the group M and M is the one of the groups M^A, M^B and M^crepresented below

wherein A represents a bond, CH=CH or C=C; 15 U represents CH or N;

V represents CH;

W represents CH orN;

-272015226250 05 Nov 2018

R^1A represents H or halogen;

R^2A represents H, (Ci-C3)alkoxy or halogen;

R^3A represents H, halogen, (Ci-C3)alkoxy, hydroxy(C2-C4)alkoxy, hydroxy(Ci-C4)alkyl,

1,2-dihydroxyethyl, l-hydroxy-2,2-difluoroethyl, methylsulfonamidomethyl, 3-hydroxy-

3-methylbut-l-yn-l-yl, 2-hydroxyacetamido, (carbamoyloxy)methyl, 1-aminocyclopropyl,

-hydroxymethyl-cycloprop-1 -yl, 1 -aminomethyl-cycloprop-1 -yl,

3-hydroxyoxetan-3-yl, 3-(hydroxy(Ci-C3)alkyl)oxetan-3-yl, 3-aminooxetan-3-yl,

4-aminopiperidin-l-yl, [4-7V-(Ci-C3)alkylpiperazin-l-yl](Ci-C3)alkyl, morpholin-4-yl(Ci-C2)alkyl, 3-[hydroxy(C2-C3)alkyl]-2-oxo-imidazolidin-l-yl or (4-hydroxypiperidinyl)methyl;

R^1B represents 3-hydroxyoxetan-3-yl, hydroxy(Ci-C3)alkyl, amino(Ci-C3)alkyl,

-aminocyclopropyl, 1 -hydroxymethyl-cycloprop-1 -yl, 1 -(carbamoyloxy )methyl15 cycloprop-1 -yl, 1 -((((phosphonooxy)methoxy)carbonyl)oxymethyl)-cycloprop-1 -yl, trans-2 -hydroxymethyl-cycloprop-1 -yl, 1 -fluoro-2 -hydroxymethyl-cycloprop-1 -yl,

2-fluoro-2-hydroxymethyl-cycloprop-l-yl, 1-methyl-2-hydroxymethyl-cycloprop-1-yl,

2-hydroxymethyl-2-methylcycloprop-1 -yl, 1 -(hydroxymethyl)cyclobut-1 -yl, l-(2-hydroxyacetyl)-azetidin-3-yl, /ra/7.s-(cz.s-3,4-dihydroxy)-cyclopcnt-l-yl,

3-hydroxymethylbicyclo[l,l,l]pentan-l-yl, 5-amino-tetrahydro-2//-pyran-2-yl or l-(oxetan-3-yl)-azetidin-3-yl; and

R^1C represents 1-aminocyclopropyl or hydroxy(Ci-C3)alkyl.

26) In a more preferred disclosure, the compounds of formula I according to disclosure 1) or 3) will be such that R¹ represents the group M and M is the one of the groups M^A, M^B25 and M^c represented below

2015226250 05 Nov 2018

wherein A represents a bond or C=C;

U represents CH;

V represents CH;

W represents CH;

R^1A represents H or fluorine;

R^2A represents H, methoxy or fluorine;

R^3A represents H, chlorine, fluorine, (Ci-C3)alkoxy, hydroxy(C2-C4)alkoxy, hydroxy(C i-C4)alkyl, 1,2-dihydroxyethyl, 1 -hydroxy-2,2-difluoroethyl, methylsulfonamidomethyl, 2-hydroxyacetamido, (carbamoyloxy)methyl,

1-aminocyclopropyl, 1-hydroxymethyl-cycloprop-l-yl, 1 -(carbamoyloxy )methylcycloprop-1 -yl, irans-2-hydroxymethyl-cycloprop-1 -yl, 1 -(hydroxymethyl)-cyclobut-1 -yl,

3-hydroxyoxetan-3-yl, morpholin-4-yl-(Ci-C2)alkyl or (4-hydroxypiperidinyl)methyl;

R^1B represents amino(Ci-C3)alkyl, 1-aminocyclopropyl, 1-hydroxymethyl-cycloprop-l-yl,

Zrans-2-hydroxymethyl-cycloprop-1 -yl, 1 -fluoro-2-hydroxymethyl-cycloprop-1 -yl,

2-fluoro-2-hydroxymethyl-cycloprop-l-yl, 1 -methyl-2 -hydroxymethyl-cycloprop-l-yl,

2-hydroxymethyl-2-methylcycloprop-1 -yl, 1 -(hydroxymethyl)cyclobut-1 -yl, l-(2-hydroxyacetyl)-azetidin-3-yl, /ra/7.s-(cz.s-3,4-dihydroxy)-cyclopent-l-yl,

-hydroxymethylbicyclo [1,1,1 Jpentan-1 -yl, 5-amino-tet rahyd ro-2//-pyran-2-yl or l-(oxetan-3-yl)-azetidin-3-yl; and

R^1C represents 1-aminocyclopropyl.

-292015226250 05 Nov 2018

27) In an even more preferred disclosure, the compounds of formula I according to disclosure 1) or 3) will be such that R¹ represents the group M and M is the one of the groups M^A and M^B represented below

R^1A

_R3A

M^A M^b wherein A represents C=C;

U represents CH;

V represents CH;

R^1A represents H;

R^2A represents H;

R^3A represents hydroxy(Ci-C4)alkyl, (carbamoyloxy)methyl, 1-aminocyclopropyl, 10 1-hydroxymethyl-cycloprop-l-yl, l-(carbamoyloxy)methyl-cycloprop-l-yl or irans-2-hydroxymethyl-cycloprop-1 -yl; and

R^1B represents irans-2-hydroxymethyl-cycloprop-l-yl, 1 -fluoro-2-hydroxymethylcycloprop-1 -yl, 2-fluoro-2-hydroxymethyl-cycloprop-1 -yl, 1 -methyl-2-hydroxymethylcycloprop-1 -yl, 2-hydroxymethyl-2-methyl cycloprop-1 -yl, trans-(cis-3,4-dihydroxy)15 cyclopent-1-yl or 3-hydroxymethylbicyclo[l,l,l]pentan-l-yl.

28) According to one variant of disclosure 27), the compounds of formula I according to disclosure 27) will be such that M is the group M^A.

29) According to the other variant of disclosure 27), the compounds of formula I according to disclosure 27) will be such that M is the group M^B.

2015226250 05 Nov 2018

30) Besides, the compounds of formula I according to disclosure 2) or 4) will preferably be such that R¹ represents the group M and M is the one of the groups M^A and M^B represented below

R^1A

_R3A

M^A M^b wherein A represents a bond, CH=CH or C=C;

U represents CH or N;

V represents CH;

R^1A represents H or halogen;

R^2A represents H, (Ci-C3)alkoxy or halogen;

R^3A represents H, (Ci-C3)alkoxy, hydroxy(C2-C4)alkoxy, hydroxyfCi-Cfialkyl, 3-hydroxy10 3-methylbut-l-yn-l-yl, 2-hydroxyacetamido, (carbamoyloxy)methyl, 1 -hydroxymethylcycloprop-1 -yl, 1 -aminomethyl-cycloprop-1 -yl, 1 -(carbamoyl oxy)methyl-cycloprop-1 -yl, l-(morpholin-4-yl)methylcycloprop-l-yl, /ra/7.s-2-hydroxymethyl-cycloprop-l-yl,

1,2-dihydroxyethyl, 3-hydroxyoxetan-3-yl, [4-7V-(Ci-C3)alkylpiperazin-l-yl](Ci-C3)alkyl, morpholin-4-yl-(Ci-C2)alkyl or 3-[hydroxy(C2-C3)alkyl]-2-oxo-imidazolidin-l-yl; and

R^1B represents 3-hydroxyoxetan-3-yl, hydroxy(Ci-C3)alkyl, amino(Ci-C3)alkyl, 1 -hydroxymethyl-cycloprop-1 -yl, /ra/7.s-2-hydiOxymethyl-cycloprop-1 -yl,

7ra/7s-(c/x-3,4-dihydroxy)-cyclopent-1 -yl or 3-hydroxymethylbicyclo[ 1,1,1 Jpentan- 1-yl.

- 31 31) The compounds of formula I according to disclosure 2) or 4) will more preferably be such that R¹ represents the group M and M is the one of the groups M^A and M^B represented below

2015226250 05 Nov 2018 r1A

R3A

M^A M^b wherein A represents a bond or C=C;

U represents CH;

V represents CH;

R^1A represents H or fluorine;

R^2A represents H, methoxy or fluorine;

R^3A represents H, (Ci-C3)alkoxy, hydroxy(C2-C4)alkoxy, hydroxy(Ci-C4)alkyl, 10 2-hydroxyacetamido, (carbamoyloxy)methyl, 1-hydroxymethyl-cycloprop-l-yl,

-(carbamoyloxy)methyl-cycloprop-1 -yl, iraws-2-hyd roxymet hyl-cycloprop-1 -yl,

1,2-dihydroxyethyl, 3-hydroxyoxetan-3-yl or morpholin-4-yl-(Ci-C2)alkyl; and

R^1B represents amino(Ci-C3)alkyl, 1-hydroxymethyl-cycloprop-l-yl, ira«5-2-hydroxymethyl-cycloprop-1 -yl, trans-(cis-3,4-dihydroxy)-cyclopent-1 -yl or

3-hydroxymethylbicyclo [1,1,1 Jpentan-1 -yl.

-322015226250 05 Nov 2018

32) Even more preferably, the compounds of formula I according to disclosure 2) or 4) will be such that R¹ represents the group M and M is the one of the groups M^A and M^Brepresented below

R^1A

_R3A

M^A M^b wherein A represents C=C;

U represents CH;

V represents CH;

R^1A represents H;

R^2A represents H;

R^3A represents hydroxyfCi-Cfialkyl, (carbamoyloxy)methyl, 1-hydroxymethyl-cycloprop10 1-yl, l-(carbamoyloxy)methyl-cycloprop-l-yl or /ra/7.s-2-hydroxymethyl-cycloprop-l-yl;

and

R^1B represents /ra/7.s-2-hydroxymethyl-cycloprop-l-yl, trans-(cis-3,4-dihydroxy)cyclopent-l-yl or 3-hydroxymethylbicyclo[l,l,l]pentan-l-yl.

33) According to one variant of disclosure 32), the compounds of formula I according to 15 disclosure 32) will be such that M is the group M^A.

34) According to the other variant of disclosure 32), the compounds of formula I according to disclosure 32) will be such that M is the group M^B.

35) Described herein are compounds of formula I as defined in one of disclosures 1) to 34) as well as to isotopically labelled, especially ²H (deuterium) labelled compounds of formula I as defined in one of disclosures 1) to 34), which compounds are identical to the compounds of formula I as defined in one of disclosures 1) to 34) except that one or more atoms has or have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Isotopically labelled, especially ²H (deuterium) labelled compounds of formula I and salts (in particular

- 33 2015226250 05 Nov 2018 pharmaceutically acceptable salts) thereof are thus within the scope of the present disclosure. Substitution of hydrogen with the heavier isotope ²H (deuterium) may lead to greater metabolic stability, resulting e.g. in an increased in-vivo half-life, reduced dosage requirements, or an improved safety profile. In one variant, the compounds of formula I are 5 not isotopically labelled, or they are labelled only with one or more deuterium atoms.

Isotopically labelled compounds of formula I may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.

36) Particularly preferred are the following compounds of formula I as defined in 10 disclosure 1) or 2):

- (/?)-4-(6-(2-fluoiO-4-methoxyphenyl)-3-oxo-l//-pyriOlo[l,2-c]imidazol-2(3//)-yl)- ,V- hy d rox y-2 -methy 1-2 -(methylsulfonyl)butanamide;

- (7?)-/V-hydroxy-4-(6-((4-(3-hydroxyoxetan-3-yl)phenyl)ethynyl)-3-oxol//-pyrrolo[l ,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-/V-hydroxy-4-(6-((4-(hydroxymethyl)phenyl)ethynyl)-3-oxol//-pyrrolo[l ,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-/V-hydroxy-4-(6-((3-hydroxyoxetan-3-yl)buta-1,3-diyn-l -yl)-3-oxo- l//-pyrrolo[l ,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-/V-hydroxy-4-(6-((4-((7/?,2/?)-2-(hydroxymethyl)cyclopropyl)phenyl)ethynyl)-3-oxo-

I //-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-/V-hydroxy-4-(6-((4-((7S',2S)-2-(hydroxymethyl)cyclopropyl)phenyl)ethynyl)-3-oxol//-pyrrolo[l ,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-/V-hydroxy-4-(6-((4-( 1 -(hydroxymethyl)cyclopropyl)phenyl)ethynyl)-3-oxolW-pyrrolo[l,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (/()-4-(6-((4-( I -(aminomethyl)cyclopropyl)phenyl)ethynyl )-3-oxoI //-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-/V-hydroxy-2-methyl-2-(methylsulfbnyl) butanamide;

- (7?)-/V-hydroxy-4-(6-((4-(l-hydroxy-2-methylpropan-2-yl)phenyl)ethynyl)-3-oxo- //-pyrrol o[ 1,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfbnyl)butanamide;

- (7?)-/V-hydroxy-4-(6-((4-(2-hydroxypropan-2-yl)phenyl)ethynyl)-3-oxo-

1 //-pyrrol o[ 1,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfbnyl)butanamide;

- (7?)-4-(6-((S)-5,6-dihydroxyhexa-1,3-diyn-l-yl)-3-oxo-1 //-pyrrolo[ 1,2-c]imidazol-

2(377)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

-342015226250 05 Nov 2018

- (R)-Vhydroxy-4-(6-(5-((7S,2S)-2-(hydroxymethyl)cyclopropyl)penta-l,3-diyn-l-yl)-

3-oxo-l//-pyrrolo[l,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (/?)-.V-hydroxy-4-(6-((4-((/?)-1 -hydroxyethyl)phenyl)ethynyl)-3-oxo17/-pyrrolo[l,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (R)-JV-hydroxy-4-(6-((4-((S)-1 -hydroxyethyl)phenyl)ethynyl)-3-oxo17/-pyrrolo[l,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (/?)-/V-hydroxy-4-(6-(( 1 -(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1 -yl)-3-oxo17/-pyrrolo[l,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (/?)-/V-hydroxy-4-(6-((4-(2-hydroxyethyl)phenyl)ethynyl)-3-oxo-

17/-pyrrolo[l,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (R)-4-(6-((4-((R)-l,2-dihydroxyethyl)phenyl)ethynyl)-3-oxo-17/-pyrrolo[l,2-c]imidazol2(3//)-yl)-/V-hydroxy-2-methyl-2-(methylsulfbnyl)butanamide;

- (R)-4-(6-((4-((S)-l,2-dihydroxyethyl)phenyl)ethynyl)-3-oxo-17/-pyrrolo[l,2-c]imidazol2(3//)-yl)-JV-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (R)-4-(6-((2-fluoro-4-(l-(hydroxymethyl)cyclopropyl)phenyl)ethynyl)-3-oxol//-pyrrolo[l ,2-c]imidazol-2(3//)-yl)-JV-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (/?)-/V-hydroxy-4-(6-((4-(3-(2-hydroxyethyl)-2-oxoimidazolidin-l-yl)phenyl)ethynyl)-

3- oxo-l//-pyrrolo[l,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (R)-4-(6-((3-fluoro-4-(2-hydroxyacetamido)phenyl)ethynyl)-3-oxo-

I //-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-JV-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (R)JV-hydroxy-4-(6-((4-(2-hydroxyethoxy)phenyl)ethynyl)-3-oxo77/-pyrrolo[l,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (R)JV-hydroxy-4-(6-((6-( 1 -(hydroxymethyl)cyclopropyl)pyridin-3-yl)ethynyl)-3-oxo17/-pyrrolo[l,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (/?)-/V-hydroxy-4-(6-((5-(I -(hydroxymethyl)cyclopropyl)pyridin-2-yl)cthynyl)-3-oxo17/-pyrrolo[l,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (R)JV-hydroxy-2-methyl-2-(methylsulfonyl)-

4- (6-((4-(morpholinomethyl)phenyl)ethynyl)-3-oxo- I//-pyrrolo[ 1,2-c]imidazol- (3 //)-yl )bu tanami d c;

- (R)-/V-hydroxy-2-methyl-2-(methylsulfonyl)4-(6-((4-(l-(morpholinomethyl)cyclopropyl)phenyl)ethynyl)-3-oxo17/-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)butanamide;

- 35 2015226250 05 Nov 2018

- (7?)-7V-hydroxy-4-(6-(((77?,27?)-2-(hydroxymethyl)cyclopropyl)buta-l,3-diyn-l-yl)-3-oxo-

I//-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfbnyl)butanamide;

- (7?)-4-(6-(2-fluoro-3-methoxyphenyl)-3-oxo-17/-pyrrolo[l,2-c]imidazol-2(3//)-yl)-

A'-h yd roxy-2 -methy 1-2 -(methylsulfonyl)butanamide;

- (J?)-(E)-7V-hydroxy-4-(6-(4-(hydroxymethyl)styryl)-3-oxo-1 //-pyrrolo[ 1,2-c]imidazol2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-7V-hydroxy-4-(6-(4-(3-(hydroxymethyl)bicyclo[l. 1.l]pentan-l-yl)cyclobuta-l,3-dien- l-yl)-3-oxo-lZ/-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-4-(6-(5-amino-5-methylhexa-1,3-diyn-1 -yl)-3-oxo-1 //-pyrrol o [ 1,2-c]imidazol-

2(3//)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (J?)-4-((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-3-oxo-

2,3-dihydro-I //-pyrrolof 1,2-c]imidazol-6-yl)ethynyl)benzyl carbamate;

- S,3R,4S)-3,4-dihydroxycyclopentyl)buta- 1,3-diyn-l-yl)-3-oxolZ/-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (J?)-(l-(4-((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-3-oxo-

2,3-dihydro-I //-pyrrolof 1,2-c]imidazol-6-yl)ethynyl)phenyl)cyclopropyl)methyl carbamate;

as well as the salts (in particular the pharmaceutically acceptable salts) thereof.

37) Also particularly preferred are the following compounds of formula I as defined in disclosure 1):

- (7?)-(l-((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-3-oxo-

2.3- dihydro-I //-pyrrolof 1,2-c] imidazol-6-yl)buta-1,3-diyn-1 -yl)cyclopropyl)methyl carbamate;

- (7?)-2V-hydroxy-4-(6-(((77?,27?)-2-(hydroxymethyl)-l-methylcyclopropyl)buta-l,3-diyn- l-yl)-3-oxo-l//-pyrrolo[l ,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfbnyl)butanamide;

- (7?)-(l-(4-((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-3-oxo-

2.3- dihydro-17/-pyrrolo[l,2-c]imidazol-6-yl)ethynyl)phenyl)cyclopropyl)methyl dimethylglycinate;

- (Λ)-4-(6-(( 1 -aminocyclopropyl)buta-1,3-diyn-1 -y 1)-3-oxo- I //-pyrrolo[ 1,2-c]imidazol-

2(3//)-yl)-/V-hydroxy-2-methyl-2-(methylsulfbnyl)butanamide;

- (7?)-4-(6-((3-aminooxetan-3-yl)buta-l,3-diyn-l-yl)-3-oxo-17/-pyrrolo[l,2-c]imidazol-

2(3//)-yl)-A'-hydroxy-2-methyl-2-(methylsulfbnyl)butanamide;

-362015226250 05 Nov 2018

- (R)-7V-hydroxy-4-(6-((4-(l-(hydroxymethyl)cyclobutyl)phenyl)ethynyl)-3-oxo7W-pyrrolo[l,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (R)-4-(6-(2-fluoro-4-(2-hydroxyethoxy)phenyl)-3-oxo- I //-pyrrolo[ 1,2-c]imidazol2(3//)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (Λ)-4-(6-(((2Λ,3S)-2,3-bis(hydroxymethyl)cyclopropyl)buta-l,3-diyn-l-yl)-3-oxolW-pyrrolo[l,2-c]imidazol-2(377)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (R)-4-(6-(4-((R)-2,3-dihydroxypropoxy)-2-fluorophenyl)-3-oxolW-pyrrolo[l,2-c]imidazol-2(377)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-4-(6-((4-(l, 1 -difluoro-2-hydroxyethyl)phenyl)ethynyl)-3-oxo-

I //-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-7V-hydroxy-4-(6-((4-(2-hydroxyacetyl)phenyl)ethynyl)-3-oxolW-pyrrolo[l,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-4-(6-(5-(dimethylamino)penta-l,3-diyn-l-yl)-3-oxo-l//-pyrrolo[l,2-c]imidazol2(377)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- methyl (R)-3-fluoro-4-(2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)3-oxo-2,3-dihydro-l//-pyrrolo[l,2-c]imidazol-6-yl)benzoate;

- (7?)-4-(6-(4-chloro-2-fluorophenyl)-3-oxo-1 //-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-

7V-hy droxy-2 -methy 1-2 -(methylsulfonyl)butanamide;

- (7?)-4-(6-(2-chloro-4-ethoxyphenyl)-3-oxo-l//-pyrrolo[l,2-c]imidazol-2(3//)-yl)-

0 /V-hy droxy-2 -methy 1-2 -(methylsulfonyl)butanamide;

- (R)-(l-((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-3-oxo-

2,3-dihydro-l//-pyrrolo[l,2-c]imidazol-6-yl)buta-l,3-diyn-l-yl)cyclopropyl)methyl dimethylglycinate;

- (7?)-(l-((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-3-oxo-

2,3-dihydro-l//-pyrrolo[l,2-c]imidazol-6-yl)buta-l,3-diyn-l-yl)cyclopropyl)methyl dihydrogen phosphate;

- (7?)-4-(6-(2-chloro-4-methoxyphenyl)-3-oxo-l//-pyrrolo[l,2-c]imidazol-2(377)-yl)7V-hy droxy-2 -methy 1-2 -(methylsulfonyl)butanamide;

- (R)-4-(6-(2-fluoro-4-(trifluoromethyl)phenyl)-3-oxo-1 //-pyrrol o [ 1,2-c]imidazol-

2(3//)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-/V-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(2,3,4-trifluorophenyl)l//-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)butanamide;

2015226250 05 Nov 2018

- (7?)-4-(6-(2,3-difluoro-4-methoxyphenyl)-3-oxo-177-pyrrolo[l,2-c]imidazol-2(377)-yl)- ,V- hy d rox y-2 -methy 1-2 -(methylsulfonyl)butanamide;

- (7?)-/V-hydroxy-4-(6-(( 1 -(hydroxymethyl)cyclobutyl)buta-1,3-diyn-1 -yl)-3-oxolW-pyrrolo[l,2-c]imidazol-2(377)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- ((7?)-/V-hydroxy-4-(6-((3-(hydroxymethyl)oxetan-3-yl)buta-l,3-diyn-l-yl)-3-oxolW-pyrrolo[l,2-c]imidazol-2(377)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-/V-hydroxy-2-methyl-4-(6-(5-(methylsulfonamido)penta-l,3-diyn-l-yl)-3-oxolW-pyrrolo[l,2-c]imidazol-2(3//)-yl)-2-(methylsulfonyl)butanamide;

- teri-butyl (7?)-3-hydroxy-3-(4-((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-

4-oxobutyl)-3-oxo-2,3-dihydro-I //-pyrrolof 1,2-c]imidazol-6-yl)ethynyl)phenyl)azetidine-

1-carboxylate;

- (27?)-4-(6-(5-cyclobutyl-6-hydroxyhexa-1,3-diyn-1 -yl)-3-oxo-I //-pyrrolof 1,2-c]imidazol2(377)-yl)-/V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-/V-hydroxy-4-(6-(((77?,25)-2-(hydroxymethyl)-2-methylcyclopropyl)buta-1,3-diyn- l-yl)-3-oxo-177-pyrrolo[l,2-c]imidazol-2(377)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-/V-hydroxy-4-(6-((l-(2-hydroxyacetyl)azetidin-3-yl)buta-l,3-diyn-l-yl)-3-oxo177-pyrrolo[l,2-c]imidazol-2(377)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-/V-hydroxy-4-(6-(5 -(3-hydroxyoxetan-3-yl)penta-1,3-diyn-1 -y 1)-3-oxo177-pyrrolo[l,2-c]imidazol-2(377)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (/?)-A'-hydiOxy-4-(6-((4-hydiOxytetrahydiO-2//-pyran-4-yl)buta-1,3-diyn-1 -yl)-3-oxo177-pyrrolo[l,2-c]imidazol-2(377)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-4-(6-(((25,5/?)-5-aminotetrahydro-2//-pyran-2-yl)buta-1,3-diyn-1 -y 1)-3-oxo177-pyrrolo[l,2-c]imidazol-2(377)-yl)-/V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-4-(6-(((77?,27?)-l-fluoro-2-(hydroxymethyl)cyclopropyl)buta-l,3-diyn-l-yl)-3-oxo-

I //-pyrrolo[ 1,2-c]imidazol-2(377)-yl)-/V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- ¢5)-4-(6-(((75,25)-l-fluoro-2-(hydroxymethyl)cyclopropyl)buta-l,3-diyn-l-yl)-3-oxo177-pyrrolo[l,2-c]imidazol-2(377)-yl)-/V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- ¢5)-4-(6-((5-(1-aminocyclopropyl)thiophen-2-yl)ethynyl)-3-oxo177-pyrrolo[l,2-c]imidazol-2(377)-yl)-/V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-4-(6-((4-(3-aminooxetan-3-yl)phenyl)ethynyl)-3-oxo-17/-pyrrolo[l,2-c]imidazol2(377)-yl)-/V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-/V-hydroxy-4-(6-((4-(3-(hydroxymethyl)oxetan-3-yl)phenyl)ethynyl)-3-oxo177-pyrrolo[l,2-c]imidazol-2(377)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- 38 2015226250 05 Nov 2018

- (R)-7V-hydroxy-4-(6-((4-(2-hydroxyacetamido)phenyl)ethynyl)-3-oxol//-pyrrolo[l,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (R)-4-(6-((4-(l-aminocyclopropyl)phenyl)ethynyl)-3-oxo-17/-pyrrolo[l,2-c]imidazol2(3//)-yl)-/V-hydroxy-2-methyl-2-(methylsulf'onyl)butanamide;

- (R)-7V-hydroxy-4-(6-(5-((7s,V?)-l-hydroxy-3-(hydroxymethyl)cyclobutyl)penta-l,3-diyn- l-yl)-3-oxo-l//-pyrrolo[l,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (phosphonooxy)methyl (R)-(l-((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-

4-oxobutyl)-3-oxo-2,3-dihydro-l//-pyrrolo[l,2-c]imidazol-6-yl)buta-l,3-diyn-

-yl)cyclopropyl)carbamate;

- (R)-(l-((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-3-oxo-

2.3- dihydro-1 //-pyrrolo[ 1,2-c]imidazol-6-yl)buta-1,3-diyn-l -yl)cyclopropyl)methyl ((phosphonooxy)methyl) carbonate;

- (R)-7V-hydroxy-4-(6-((2-(2-hydroxypropan-2-yl)thiazol-5-yl)ethynyl)-3-oxo-

I//-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulf'onyl)butanamide;

- (R)-4-(6-((4-((4-aminopiperidin-l-yl)methyl)phenyl)ethynyl)-3-oxoI//-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-/V-hydroxy-2-methyl-2-(methylsulf'onyl)butanamide;

- (7?)-4-(6-(((7R,2R)-2-fluoro-2-(hydroxymethyl)cyclopropyl)buta-l,3-diyn-l-yl)-3-oxo-

I//-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-,V-hydroxy-2-methyl-2-(methylsulf'onyl)butanamide;

- (R)-4-(6-(((7S,2S)-2-fluoro-2-(hydroxymethyl)cyclopropyl)buta-l,3-diyn-l-yl)-3-oxo-

I //-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-/V-hydroxy-2-methyl-2-(methylsulf'onyl)butanamide;

- (R)-7V-hydroxy-4-(6-((4-((4-hydroxypiperidin-1 -yl)methyl)phenyl)ethynyl)-3-oxo-

I//-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulf'onyl)butanamide;

- (R)-4-(6-((4-(4-aminopiperidin-l-yl)phenyl)ethynyl)-3-oxo-1 //-pyrrolo[ 1,2-c]imidazol2(3//)-yl)-/V-hydroxy-2-methyl-2-(methylsulf'onyl)butanamide;

- (R)-7V-hydroxy-2-methyl-4-(6-((4-(methylsulfonamidomethyl)phenyl)ethynyl)-3-oxol//-pyrrolo[l,2-c]imidazol-2(3//)-yl)-2-(methylsulfonyl)butanamide;

- (R)-7V-hydroxy-2-methyl-2-(methylsulfonyl)-4-(6-((l-(oxetan-3-yl)azetidin-3-yl)buta-

1.3- diyn-l -yl)-3-oxo- I//-pyrrolo[ 1,2-c]imidazol-2(377)-yl)butanamide;

-392015226250 05 Nov 2018

38) Further preferred are the following compounds of formula I as defined in disclosure 1) or 2):

- (7?)-7V-hydroxy-4-(6-(4-(3-hydroxyoxetan-3-yl)phenyl)-3-oxo-I //-pyrrol o[ 1,2-c]imidazol2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (/?)-4-(6-((4-(2-ethoxypropan-2-yl)phenyl)ethynyl)-3-oxo-l//-pyrrolo[l,2-c]imidazol2(3//)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (/?)-4-(6-((2-fluoro-4-(hydroxymethyl)phenyl)ethynyl)-3-oxo-l//-pyrrolo[l,2-c]imidazol2(3//)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (/?)-A'-hyd roxy-4-(6-(4-(3-hyd roxy-3 -methylbut-1 -yn-1 -yl)phenyl)-3 -oxo- l//-pyrrolo[l,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (/?)-A-hydroxy-4-(6-(5-hydroxy-5-methylhexa-1,3-diyn-l-yl)-3-oxol//-pyrrolo[l,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (/?)-A'-hydiOxy-2-methyl-4-(6-((4-((4-methylpiperazin-1 -yl)methyl)phenyl)ethynyl)3-oxo-l//-pyrrolo[l,2-c]imidazol-2(3//)-yl)-2-(methylsulfonyl)butanamide;

- (/?)-7V-hydroxy-4-(6-(4-(2-hydroxyethoxy)phenyl)-3-oxo-l//-pyrrolo[l,2-c]imidazol2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (/?)-7V-hydroxy-4-(6-(4-(2-methoxyethoxy)phenyl)-3-oxo- I //-pyrrolo[ 1,2-c]imidazol-

2(3//)-yl)-2-methyl-2-(methylsulfbnyl)butanamide;

39) Also further preferred are the following compounds of formula I as defined in disclosure 1):

- (/?)-4-(6-(2-fluoro-4-methylphenyl)-3-oxo-l//-pyrrolo[l,2-c]imidazol-2(3//)-yl)-

A-hyd rox y-2 -methy 1-2 -(methylsulfonyl)butanamide;

- (/?)-4-(6-(3-fluoro-4-isopropoxyphenyl)-3-oxo-l//-pyrrolo[l,2-c]imidazol-2(3//)-yl)-

5 A-hyd rox y-2 -methy 1-2 -(methylsulfonyl)butanamide;

40) Described herein are compounds of formula I as defined in disclosure 1) or 3) which are selected from the group consisting of the compounds listed in disclosure 36), the compounds listed in disclosure 37), the compounds listed in disclosure 38) and the 30 compounds listed in disclosure 39). In particular, it also relates to the groups of compounds of formula I selected from the group consisting of the compounds listed in disclosure 36),

-402015226250 05 Nov 2018 the compounds listed in disclosure 37), the compounds listed in disclosure 38) and the compounds listed in disclosure 39), which groups of compounds furthermore correspond to one of disclosures 2) to 34), as well as to the salts (in particular the pharmaceutically acceptable salts) of such compounds. The disclosure moreover relates to any individual 5 compound of formula I selected from the group consisting of the compounds listed in disclosure 36), the compounds listed in disclosure 37), the compounds listed in disclosure 38) and the compounds listed in disclosure 39), and to the salts (in particular the pharmaceutically acceptable salts) of such individual compound.

The compounds of formula I described herein, i.e. according to one of disclosures 1) to 40) 10 above, exhibit antibacterial activity, especially against Gram-negative organisms and are therefore suitable to treat bacterial infections in mammals, especially humans. Said compounds may also be used for veterinary applications, such as treating infections in livestock and companion animals. They may further constitute substances for preserving inorganic and organic materials in particular all types of organic materials for example 15 polymers, lubricants, paints, fibres, leather, paper and wood.

They may therefore be used for the treatment or prevention of infectious disorders caused by fermentative or non-fermentative gram negative bacteria, especially those caused by susceptible and multi-drug resistant Gram-negative bacteria. Examples of such Gramnegative bacteria include Acinetobacter spp. such as Acinetobacter baumannii or 20 Acinetobacter haemolyticus, Actinobacillus actinomycetemcomitans, Achromobacter spp.

such as Achromobacter xylosoxidans or Achromobacter faecalis, Aeromonas spp. such as Aeromonas hydrophila, Bacteroides spp. such as Bacteroides fragilis, Bacteroides theataioatamicron, Bacteroides distasonis, Bacteroides ovatus or Bacteroides vulgatus, Bartonella hensenae, Bordetella spp. such as Bordetella pertussis, Borrelia spp. such as 25 Borrelia Burgdorferi, Brucella spp. such as Brucella melitensis, Burkholderia spp. such as

Burkholderia cepacia, Burkholderia pseudomallei or Burkholderia mallei, Campylobacter spp. such as Campylobacter jejuni, Campylobacter fetus or Campylobacter coli, Cedecea, Chlamydia spp. such as Chlamydia pneumoniae, Chlamydia trachomatis, Citrobacter spp. such as Citrobacter diversus (koseri) or Citrobacter freundii, Coxiella burnetii, 30 Edwardsiella spp. such as Edwarsiella tarda, Ehrlichia chafeensis, Eikenella corrodens,

Enterobacter spp. such as Enterobacter cloacae, Enterobacter aerogenes, Enterobacter agglomerans, Escherichia coli, Francisella tularensis, Fusobacterium spp., Haemophilus

-41 2015226250 05 Nov 2018 spp. such as Haemophilus influenzae (beta-lactamase positive and negative) or Haemophilus ducreyi, Helicobacter pylori, Kingella kingae, Klebsiella spp. such as Klebsiella oxytoca, Klebsiella pneumoniae (including those encoding extended-spectrum beta-lactamases (hereinafter ESBLs), carbapenemases (KPCs), cefotaximase-Munich 5 (CTX-M), metallo-beta-lactamases, and AmpC-type beta-lactamases that confer resistance to currently available cephalosporins, cephamycins, carbapenems, beta-lactams, and beta-lactam/beta-lactamase inhibitor combinations), Klebsiella rhinoscleromatis or Klebsiella ozaenae, Legionella pneumophila, Mannheimia haemolyticus, Moraxella catarrhalis (beta-lactamase positive and negative), Morganella morganii, Neisseria spp.

such as Neisseria gonorrhoeae or Neisseria meningitidis, Pasteurella spp. such as Pasteurella multocida, Plesiomonas shigelloides, Porphyromonas spp. such as Porphyromonas asaccharolytica, Prevotella spp. such as Prevotella corporis, Prevotella intermedia or Prevotella endodontalis, Proteus spp. such as Proteus mirabilis, Proteus vulgaris, Proteus penneri or Proteus myxofaciens, Porphyromonas asaccharolytica, 15 Plesiomonas shigelloides, Providencia spp. such as Providencia stuartii, Providencia rettgeri or Providencia alcalifaciens, Pseudomonas spp. such as Pseudomonas aeruginosa (including ceftazidime-, cefpirome- and cefepime-resistant P. aeruginosa, carbapenem-resistant P. aeruginosa or quinolone-resistant P. aeruginosa) or Pseudomonas fluorescens, Ricketsia prowazekii, Salmonella spp. such as Salmonella typhi or Salmonella 20 paratyphi, Serratia marcescens, Shigella spp. such as Shigella flexneri, Shigella boydii, Shigella sonnei or Shigella dysenteriae, Streptobacillus moniliformis, Stenotrophomonas maltophilia, Treponema spp., Vibrio spp. such as Vibrio cholerae, Vibrio parahaemolyticus, Vibrio vulnificus, Vibrio alginolyticus, Yersinia spp. such as Yersinia enterocolitica, Yersinia pestis or Yersinia pseudotuberculosis.

The compounds of formula I according to this disclosure are thus useful for treating a variety of infections caused by fermentative or non-fermentative Gram-negative bacteria, especially infections such as: nosocomial pneumonia (related to infection by Legionella pneumophila, Haemophilus influenzae, or Chlamydia pneumonia)', urinary tract infections; systemic infections (bacteraemia and sepsis); skin and soft tissue infections (including burn 30 patients); surgical infections; intraabdominal infections; lung infections (including those in patients with cystic fibrosis); Helicobacter pylori (and relief of associated gastric complications such as peptic ulcer disease, gastric carcinogenesis, etc.); endocarditis;

-422015226250 05 Nov 2018 diabetic foot infections; osteomyelitis; otitis media, sinusitus, bronchitis, tonsillitis, and mastoiditis related to infection by Haemophilus influenzae or Moraxella catarrhalis', pharynigitis, rheumatic fever, and glomerulonephritis related to infection by Actinobacillus haemolyticum·, sexually transmitted diseases related to infection by Chlamydia 5 trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or

Neisseria gonorrheae', systemic febrile syndromes related to infection by Borrelia recurrentis·, Lyme disease related to infection by Borrelia burgdorferi·, conjunctivitis, keratitis, and dacrocystitis related to infection by Chlamydia trachomatis, Neisseria gonorrhoeae or H. influenzae', gastroenteritis related to infection by Campylobacter jejuni', 10 persistent cough related to infection by Bordetella pertussis and gas gangrene related to infection by Bacteroides spp. Other bacterial infections and disorders related to such infections that may be treated or prevented in accord with the method of the present disclosure are referred to in J. P. Sanford et al., The Sanford Guide to Antimicrobial Therapy, 26th Edition, (Antimicrobial Therapy, Inc., 1996).

The preceding lists of infections and pathogens are to be interpreted merely as examples and in no way as limiting.

The compounds of formula I according to this disclosure, or the pharmaceutically acceptable salts thereof, may therefore be used for the preparation of a medicament, and are suitable, for the prevention or treatment of a bacterial infection, in particular for the 20 prevention or treatment of a bacterial infection caused by Gram-negative bacteria, especially by multi-drug resistant Gram-negative bacteria.

The compounds of formula I according to this disclosure, or the pharmaceutically acceptable salts thereof, may thus especially be used for the preparation of a medicament, and are suitable, for the prevention or treatment of a bacterial infection caused by 25 Gram-negative bacteria selected from the group consisting of Acinetobacter baumannii,

Burkholderia spp. (e.g. Burkholderia cepacia), Citrobacter spp., Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Serratia marcescens, Stenotrophomonas maltophilia and Pseudomonas aeruginosa (notably for the prevention or treatment of a bacterial infection caused by Acinetobacter 30 baumannii bacteria, Escherichia coli bacteria, Klebsiella pneumoniae bacteria or

Pseudomonas aeruginosa bacteria, and in particular for the prevention or treatment of a

-43 2015226250 05 Nov 2018 bacterial infection mediated by quinolone-resistant Acinetobacter baumannii bacteria or quinolone-resistant Klebsiella pneumoniae bacteria).

The compounds of formula I according to this disclosure, or the pharmaceutically acceptable salts thereof, may more especially be used for the preparation of a medicament, 5 and are suitable, for the prevention or treatment of a bacterial infection caused by

Gram-negative bacteria selected from the group consisting of Citrobacter spp., Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Serratia marcescens, Stenotrophomonas maltophilia and Pseudomonas aeruginosa bacteria (notably of a bacterial infection caused by 10 Gram-negative bacteria selected from the group consisting of Klebsiella pneumoniae and

Pseudomonas aeruginosa bacteria, and in particular of a bacterial infection caused by Pseudomonas aeruginosa bacteria).

The compounds of formula I according to this disclosure, or the pharmaceutically acceptable salts thereof, may thus especially be used for the preparation of a medicament, 15 and are suitable, for the prevention or treatment of a bacterial infection selected from urinary tract infections, systemic infections (such as bacteraemia and sepsis), skin and soft tissue infections (including burn patients), surgical infections; intraabdominal infections and lung infections (including those in patients with cystic fibrosis).

The compounds of formula I according to this disclosure, or the pharmaceutically 20 acceptable salts thereof, may more especially be used for the preparation of a medicament, and are suitable, for the prevention or treatment of a bacterial infection selected from urinary tract infections, intraabdominal infections and lung infections (including those in patients with cystic fibrosis), and in particular for the prevention or treatment of a bacterial infection selected from urinary tract infections and intraabdominal infections.

Besides, the compounds of formula I according to this disclosure display intrinsic antibacterial properties and have the ability to improve permeability of the outer membrane of Gram-negative bacteria to other antibacterial agents. Their use in combination with another antibacterial agent might offer some further advantages such as lowered side-effects of drugs due to lower doses used or shorter time of treatment, more rapid cure 30 of infection shortening hospital stays, increasing spectrum of pathogens controlled, and decreasing incidence of development of resistance to antibiotics. The antibacterial agent

-442015226250 05 Nov 2018 for use in combination with a compound of formula I according to this disclosure will be selected from the group consisting of a penicillin antibiotic (such as ampicillin, piperacillin, penicillin G, amoxicillin, or ticarcillin), a cephalosporin antibiotic (such as ceftriaxone, cefatazidime, cefepime, cefotaxime) a carbapenem antibiotic (such as 5 imipenem, or meropenem), a monobactam antibiotic (such as aztreonam), a fluoroquinolone antibiotic (such as ciprofloxacin, moxifloxacin or levofloxacin), a macrolide antibiotic (such as erythromycin or azithromycin), an aminoglycoside antibiotic (such as amikacin, gentamycin or tobramycin), a glycopeptide antibiotic (such as vancomycin or teicoplanin), a tetracycline antibiotic (such as tetracycline, oxytetracycline, 10 doxycycline, minocycline or tigecycline), and linezolid, clindamycin, telavancin, daptomycin, novobiocin, rifampicin and polymyxin. Preferably, the antibacterial agent for use in combination with a compound of formula I according to this disclosure will be selected from the group consisting of vancomycin, tigecycline and rifampicin.

The compounds of formula I according to this disclosure, or the pharmaceutically acceptable salt thereof, may moreover be used for the preparation of a medicament, and are suitable, for the prevention or treatment (and especially the treatment) of infections caused by biothreat

Gram negative by the US Center for Disease bacterial pathogens can be bacterial pathogens

Control (the list of found at the as such web http://www.selectagents.gov/Select%20Agents%20and%20Toxins%20List.html), listed biothreat page and in particular by Gram negative pathogens selected from the group consisting of Yersinia pestis, Francisella tularensis (tularemia), Burkholderia pseudomallei and Burkholderia mallei.

Described herein is the use of a compound of formula I according to one of disclosures 1) 25 to 40), or of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of a bacterial infection (in particular one of the previously mentioned infections caused by Gram-negative bacteria, especially by multidrug resistant Gram-negative bacteria). Descirbed herein is a compound of formula I according to one of disclosures 1) to 40), or a pharmaceutically acceptable salt thereof, for 30 the prevention or treatment of a bacterial infection (in particular for the prevention or treatment of one of the previously mentioned infections caused by Gram-negative bacteria, especially by multi-drug resistant Gram-negative bacteria). Also described herein is a

-452015226250 05 Nov 2018 compound of formula I according to one of disclosures 1) to 40), or a pharmaceutically acceptable salt thereof, as a medicament. Also described herein is a pharmaceutical composition containing, as active ingredient, a compound of formula I according to one of disclosures 1) to 40), or a pharmaceutically acceptable salt thereof, and at least one 5 therapeutically inert excipient.

As well as in humans, bacterial infections can also be treated using compounds of formula I (or pharmaceutically acceptable salts thereof) in other species like pigs, ruminants, horses, dogs, cats and poultry.

Described herein are pharmacologically acceptable salts and to compositions and 10 formulations of compounds of formula I, Ip, Ice or Icep.

Any reference to a compound of formula I, Ip, Ice or Icep in this text is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.

A pharmaceutical composition according to the present disclosure contains at least one 15 compound of formula I (or a pharmaceutically acceptable salt thereof) as the active ingredient and optionally carriers and/or diluents and/or adjuvants, and may also contain additional known antibiotics.

The compounds of formula I and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral or parenteral 20 administration.

The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, “Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of 25 formula I or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.

-462015226250 05 Nov 2018

Described herein is a method for the prevention or the treatment of a Gram-negative bacterial infection in a patient, comprising the administration to said patient of a pharmaceutically active amount of a compound of formula I according to one of disclosures 1) to 40) or a pharmaceutically acceptable salt thereof. Accordingly, described 5 herein is a method for the prevention or the treatment of a bacterial infection caused by

Gram-negative bacteria (notably for the prevention or treatment of a bacterial infection caused by Acinetobacter baumannii bacteria, Escherichia coli bacteria, Klebsiella pneumoniae bacteria or Pseudomonas aeruginosa bacteria, and in particular for the prevention or treatment of a bacterial infection caused by quinolone-resistant 10 Acinetobacter baumannii quinolone-resistant bacteria or Klebsiella pneumoniae quinoloneresistant bacteria) in a patient, comprising the administration to said patient of a pharmaceutically active amount of a compound of formula I according to one of disclosures 1) to 40) or a pharmaceutically acceptable salt thereof.

Moreover, the compounds of formula I described herein may also be used for cleaning 15 purposes, e.g. to remove pathogenic microbes and bacteria from surgical instruments, catheters and artificial implants or to make a room or an area aseptic. For such purposes, the compounds of formula I could be contained in a solution or in a spray formulation.

Described herein are compounds of formula I as defined in disclosure 1), or further limited under consideration of their respective dependencies by the characteristics of any one of 20 disclosures 2) to 40), and to pharmaceutically acceptable salts thereof. It relates furthermore to the use of such compounds as medicaments, especially for the prevention or treatment of a bacterial infection, in particular for the prevention or treatment of a bacterial infection caused by Gram-negative bacteria (notably for the prevention or treatment of a bacterial infection caused by Acinetobacter baumannii bacteria, Escherichia coli bacteria, 25 Klebsiella pneumoniae bacteria or Pseudomonas aeruginosa bacteria, and in particular for the prevention or treatment of a bacterial infection caused by quinolone-resistant Acinetobacter baumannii quinolone-resistant bacteria or Klebsiella pneumoniae quinoloneresistant bacteria). The following disclosures relating to the compounds of formula I according to disclosure 1) are thus possible and intended and herewith specifically 30 disclosed in individualised form:

1, 2+1, 3+1, 4+3+1, 5+3+1, 5+4+3+1, 6+1, 6+2+1, 6+3+1, 6+4+3+1, 6+5+3+1, 6+5+4+3+1, 7+6+1,

7+6+2+1, 7+6+3+1, 7+6+4+3+1, 7+6+5+3+1, 7+6+5+4+3+1, 8+7+6+1, 8+7+6+2+1, 8+7+6+3+1,

-472015226250 05 Nov 2018

8+7+6+4+3+1, 8+7+6+5+3+1, 8+7+6+5+4+3+1, 9+7+6+1, 9+7+6+2+1, 9+7+6+3+1, 9+7+6+4+3+1,

9+7+6+5+3+1, 9+7+6+5+4+3+1, 10+6+1, 10+6+2+1, 10+6+3+1, 10+6+4+3+1, 10+6+5+3+1,

10+6+5+4+3+1, 11+10+6+1, 11+10+6+2+1, 11+10+6+3+1,

11+10+6+5+4+3+1,

12+10+6+5+4+3+1,

13+10+6+5+4+3+1,

11+10+6+4+3+1,

11+10+6+5+3+1,

12+10+6+1, 12+10+6+2+1,

12+10+6+3+1,

12+10+6+4+3+1,

12+10+6+5+3+1,

13+10+6+1, 13+10+6+2+1, 13+10+6+3+1, 13+10+6+4+3+1,

14+6+1, 14+6+2+1, 14+6+3+1, 14+6+4+3+1, 14+6+5+3+1,

13+10+6+5+3+1,

14+6+5+4+3+1,

15+14+6+1, 15+14+6+2+1, 15+14+6+3+1, 15+14+6+4+3+1, 15+14+6+5+3+1, 15+14+6+5+4+3+1, 16+1,

16+2+1, 16+3+1, 16+4+3+1, 16+5+3+1, 16+5+4+3+1, 17+16+1, 17+16+2+1, 17+16+3+1, 17+16+4+3+1,

17+16+5+3+1, 17+16+5+4+3+1, 18+16+1, 18+16+2+1, 18+16+3+1, 18+16+4+3+1, 18+16+5+3+1,

18+16+5+4+3+1, 19+16+1, 19+16+2+1, 19+16+3+1, 19+16+4+3+1, 19+16+5+3+1, 19+16+5+4+3+1,

20+1, 20+3+1, 21+20+1, 21+20+3+1, 22+21+20+1, 22+21+20+3+1, 23+20+1, 23+20+3+1, 24+23+20+1,

24+23+20+3+1, 25+1, 25+3+1, 26+1, 26+3+1, 27+1, 27+3+1, 28+27+1, 28+27+3+1, 29+27+1, 29+27+3+1,

30+2+1, 30+4+3+1, 31+2+1, 31+4+3+1, 32+2+1, 32+4+3+1, 33+32+2+1, 33+32+4+3+1, 34+32+2+1,

34+32+4+3+1, 35+1, 35+2+1, 35+3+1, 35+4+3+1, 35+5+3+1, 35+5+4+3+1, 35+6+1, 35+6+2+1,

35+6+3+1, 35+6+4+3+1, 35+6+5+3+1, 35+6+5+4+3+1, 35+7+6+1, 35+7+6+2+1, 35+7+6+3+1,

35+7+6+4+3+1, 35+7+6+5+3+1, 35+7+6+5+4+3+1, 35+8+7+6+1, 35+8+7+6+2+1, 35+8+7+6+3+1,

35+8+7+6+4+3+1, 35+8+7+6+5+3+1, 35+8+7+6+5+4+3+1, 35+9+7+6+1, 35+9+7+6+2+1, 35+9+7+6+3+1,

35+9+7+6+4+3+1, 35+9+7+6+5+3+1, 35+9+7+6+5+4+3+1, 35+10+6+1, 35+10+6+2+1, 35+10+6+3+1,

35+10+6+4+3+1, 35+10+6+5+3+1, 35+10+6+5+4+3+1, 35+11+10+6+1, 35+11+10+6+2+1,

35+11+10+6+3+1, 35+11+10+6+4+3+1, 35+11+10+6+5+3+1, 35+11+10+6+5+4+3+1, 35+12+10+6+1,

35+12+10+6+2+1, 35+12+10+6+3+1, 35+12+10+6+4+3+1, 35+12+10+6+5+3+1, 35+12+10+6+5+4+3+1,

35+13+10+6+1, 35+13+10+6+2+1, 35+13+10+6+3+1, 35+13+10+6+4+3+1, 35+13+10+6+5+3+1,

35+13+10+6+5+4+3+1, 35+14+6+1, 35+14+6+2+1, 35+14+6+3+1, 35+14+6+4+3+1, 35+14+6+5+3+1,

35+14+6+5+4+3+1, 35+15+14+6+1, 35+15+14+6+2+1, 35+15+14+6+3+1, 35+15+14+6+4+3+1,

35+15+14+6+5+3+1, 35+15+14+6+5+4+3+1, 35+16+1, 35+16+2+1, 35+16+3+1, 35+16+4+3+1,

35+16+5+3+1, 35+16+5+4+3+1, 35+17+16+1, 35+17+16+2+1, 35+17+16+3+1, 35+17+16+4+3+1,

35+17+16+5+3+1, 35+17+16+5+4+3+1, 35+18+16+1, 35+18+16+2+1, 35+18+16+3+1, 35+18+16+4+3+1,

35+18+16+5+3+1, 35+18+16+5+4+3+1, 35+19+16+1, 35+19+16+2+1, 35+19+16+3+1, 35+19+16+4+3+1,

35+19+16+5+3+1, 35+19+16+5+4+3+1, 35+20+1, 35+20+3+1, 35+21+20+1, 35+21+20+3+1,

35+22+21+20+1, 35+22+21+20+3+1, 35+23+20+1, 35+23+20+3+1, 35+24+23+20+1, 35+24+23+20+3+1,

35+25+1, 35+25+3+1, 35+26+1, 35+26+3+1, 35+27+1, 35+27+3+1, 35+28+27+1, 35+28+27+3+1,

35+29+27+1, 35+29+27+3+1, 35+30+2+1, 35+30+4+3+1, 35+31+2+1, 35+31+4+3+1, 35+32+2+1,

35+32+4+3+1, 35+33+32+2+1, 35+33+32+4+3+1, 35+34+32+2+1, 35+34+32+4+3+1, 36+1, 36+2+1,

36+3+1, 36+4+3+1, 36+5+3+1, 36+5+4+3+1, 36+6+1, 36+6+2+1, 36+6+3+1, 36+6+4+3+1, 36+6+5+3+1,

36+6+5+4+3+1, 36+7+6+1, 36+7+6+2+1, 36+7+6+3+1, 36+7+6+4+3+1, 36+7+6+5+3+1,

36+7+6+5+4+3+1, 36+8+7+6+1, 36+8+7+6+2+1, 36+8+7+6+3+1, 36+8+7+6+4+3+1, 36+8+7+6+5+3+1,

36+8+7+6+5+4+3+1, 36+9+7+6+1, 36+9+7+6+2+1, 36+9+7+6+3+1, 36+9+7+6+4+3+1,36+9+7+6+5+3+1,

36+9+7+6+5+4+3+1, 36+10+6+1, 36+10+6+2+1, 36+10+6+3+1, 36+10+6+4+3+1, 36+10+6+5+3+1,

36+10+6+5+4+3+1, 36+11+10+6+1, 36+11+10+6+2+1, 36+11+10+6+3+1, 36+11+10+6+4+3+1,

36+11+10+6+5+3+1, 36+11+10+6+5+4+3+1, 36+12+10+6+1, 36+12+10+6+2+1, 36+12+10+6+3+1,

-482015226250 05 Nov 2018

36+12+10+6+4+3+1, 36+12+10+6+5+3+1, 36+12+10+6+5+4+3+1, 36+13+10+6+1, 36+13+10+6+2+1,

36+13+10+6+3+1, 36+13+10+6+4+3+1, 36+13+10+6+5+3+1, 36+13+10+6+5+4+3+1, 36+14+6+1,

36+14+6+2+1, 36+14+6+3+1, 36+14+6+4+3+1, 36+14+6+5+3+1, 36+14+6+5+4+3+1, 36+15+14+6+1,

36+15+14+6+2+1, 36+15+14+6+3+1, 36+15+14+6+4+3+1, 36+15+14+6+5+3+1, 36+15+14+6+5+4+3+1,

36+16+1, 36+16+2+1, 36+16+3+1, 36+16+4+3+1, 36+16+5+3+1, 36+16+5+4+3+1, 36+17+16+1,

36+17+16+2+1, 36+17+16+3+1, 36+17+16+4+3+1, 36+17+16+5+3+1, 36+17+16+5+4+3+1, 36+18+16+1,

36+18+16+2+1, 36+18+16+3+1, 36+18+16+4+3+1, 36+18+16+5+3+1, 36+18+16+5+4+3+1, 36+19+16+1,

36+19+16+2+1, 36+19+16+3+1, 36+19+16+4+3+1, 36+19+16+5+3+1, 36+19+16+5+4+3+1, 36+20+1,

36+20+3+1, 36+21+20+1, 36+21+20+3+1, 36+22+21+20+1, 36+22+21+20+3+1, 36+23+20+1,

36+23+20+3+1, 36+24+23+20+1, 36+24+23+20+3+1, 36+25+1, 36+25+3+1, 36+26+1, 36+26+3+1,

36+27+1, 36+27+3+1, 36+28+27+1, 36+28+27+3+1, 36+29+27+1, 36+29+27+3+1, 36+30+2+1,

36+30+4+3+1, 36+31+2+1, 36+31+4+3+1, 36+32+2+1, 36+32+4+3+1, 36+33+32+2+1, 36+33+32+4+3+1,

36+34+32+2+1, 36+34+32+4+3+1, 37+1, 37+2+1, 37+3+1, 37+4+3+1, 37+5+3+1, 37+5+4+3+1, 37+6+1,

37+6+2+1, 37+6+3+1, 37+6+4+3+1, 37+6+5+3+1, 37+6+5+4+3+1, 37+7+6+1, 37+7+6+2+1, 37+7+6+3+1,

37+7+6+4+3+1, 37+7+6+5+3+1, 37+7+6+5+4+3+1, 37+8+7+6+1, 37+8+7+6+2+1, 37+8+7+6+3+1,

37+8+7+6+4+3+1, 37+8+7+6+5+3+1, 37+8+7+6+5+4+3+1, 37+9+7+6+1, 37+9+7+6+2+1, 37+9+7+6+3+1,

37+9+7+6+4+3+1, 37+9+7+6+5+3+1, 37+9+7+6+5+4+3+1, 37+10+6+1, 37+10+6+2+1, 37+10+6+3+1,

37+10+6+4+3+1, 37+10+6+5+3+1, 37+10+6+5+4+3+1, 37+11+10+6+1, 37+11+10+6+2+1,

37+11+10+6+3+1, 37+11+10+6+4+3+1, 37+11+10+6+5+3+1, 37+11+10+6+5+4+3+1, 37+12+10+6+1,

37+12+10+6+2+1, 37+12+10+6+3+1, 37+12+10+6+4+3+1, 37+12+10+6+5+3+1, 37+12+10+6+5+4+3+1,

37+13+10+6+1, 37+13+10+6+2+1, 37+13+10+6+3+1, 37+13+10+6+4+3+1, 37+13+10+6+5+3+1,

37+13+10+6+5+4+3+1, 37+14+6+1, 37+14+6+2+1, 37+14+6+3+1, 37+14+6+4+3+1, 37+14+6+5+3+1,

37+14+6+5+4+3+1, 37+15+14+6+1, 37+15+14+6+2+1, 37+15+14+6+3+1, 37+15+14+6+4+3+1,

37+15+14+6+5+3+1, 37+15+14+6+5+4+3+1, 37+16+1, 37+16+2+1, 37+16+3+1, 37+16+4+3+1,

37+16+5+3+1, 37+16+5+4+3+1, 37+17+16+1, 37+17+16+2+1, 37+17+16+3+1, 37+17+16+4+3+1,

37+17+16+5+3+1, 37+17+16+5+4+3+1, 37+18+16+1, 37+18+16+2+1, 37+18+16+3+1, 37+18+16+4+3+1,

37+18+16+5+3+1, 37+18+16+5+4+3+1, 37+19+16+1, 37+19+16+2+1, 37+19+16+3+1, 37+19+16+4+3+1,

37+19+16+5+3+1, 37+19+16+5+4+3+1, 37+20+1, 37+20+3+1, 37+21+20+1, 37+21+20+3+1,

37+22+21+20+1, 37+22+21+20+3+1, 37+23+20+1, 37+23+20+3+1, 37+24+23+20+1, 37+24+23+20+3+1,

37+25+1, 37+25+3+1, 37+26+1, 37+26+3+1, 37+27+1, 37+27+3+1, 37+28+27+1, 37+28+27+3+1,

37+29+27+1, 37+29+27+3+1, 37+30+2+1, 37+30+4+3+1, 37+31+2+1, 37+31+4+3+1, 37+32+2+1,

37+32+4+3+1, 37+33+32+2+1, 37+33+32+4+3+1, 37+34+32+2+1, 37+34+32+4+3+1, 38+1, 38+2+1,

38+3+1, 38+4+3+1, 38+5+3+1, 38+5+4+3+1, 38+6+1, 38+6+2+1, 38+6+3+1, 38+6+4+3+1, 38+6+5+3+1,

38+6+5+4+3+1, 38+7+6+1, 38+7+6+2+1, 38+7+6+3+1, 38+7+6+4+3+1, 38+7+6+5+3+1,

38+7+6+5+4+3+1, 38+8+7+6+1, 38+8+7+6+2+1, 38+8+7+6+3+1, 38+8+7+6+4+3+1, 38+8+7+6+5+3+1,

38+8+7+6+5+4+3+1, 38+9+7+6+1, 38+9+7+6+2+1, 38+9+7+6+3+1, 38+9+7+6+4+3+1, 38+9+7+6+5+3+1,

38+9+7+6+5+4+3+1, 38+10+6+1, 38+10+6+2+1, 38+10+6+3+1, 38+10+6+4+3+1, 38+10+6+5+3+1,

38+10+6+5+4+3+1, 38+11+10+6+1, 38+11+10+6+2+1, 38+11+10+6+3+1, 38+11+10+6+4+3+1,

38+11+10+6+5+3+1, 38+11+10+6+5+4+3+1, 38+12+10+6+1, 38+12+10+6+2+1, 38+12+10+6+3+1,

38+12+10+6+4+3+1, 38+12+10+6+5+3+1, 38+12+10+6+5+4+3+1, 38+13+10+6+1, 38+13+10+6+2+1,

-492015226250 05 Nov 2018

38+13+10+6+3+1, 38+13+10+6+4+3+1, 38+13+10+6+5+3+1, 38+13+10+6+5+4+3+1, 38+14+6+1,

38+14+6+2+1, 38+14+6+3+1, 38+14+6+4+3+1, 38+14+6+5+3+1, 38+14+6+5+4+3+1, 38+15+14+6+1,

38+15+14+6+2+1, 38+15+14+6+3+1, 38+15+14+6+4+3+1, 38+15+14+6+5+3+1, 38+15+14+6+5+4+3+1,

38+16+1, 38+16+2+1, 38+16+3+1, 38+16+4+3+1, 38+16+5+3+1, 38+16+5+4+3+1, 38+17+16+1,

38+17+16+2+1, 38+17+16+3+1, 38+17+16+4+3+1, 38+17+16+5+3+1, 38+17+16+5+4+3+1, 38+18+16+1,

38+18+16+2+1, 38+18+16+3+1, 38+18+16+4+3+1, 38+18+16+5+3+1, 38+18+16+5+4+3+1, 38+19+16+1,

38+19+16+2+1, 38+19+16+3+1, 38+19+16+4+3+1, 38+19+16+5+3+1, 38+19+16+5+4+3+1, 38+20+1,

38+20+3+1, 38+21+20+1, 38+21+20+3+1, 38+22+21+20+1, 38+22+21+20+3+1, 38+23+20+1,

38+23+20+3+1, 38+24+23+20+1, 38+24+23+20+3+1, 38+25+1, 38+25+3+1, 38+26+1, 38+26+3+1,

38+27+1, 38+27+3+1, 38+28+27+1, 38+28+27+3+1, 38+29+27+1, 38+29+27+3+1, 38+30+2+1,

38+30+4+3+1, 38+31+2+1, 38+31+4+3+1, 38+32+2+1, 38+32+4+3+1, 38+33+32+2+1, 38+33+32+4+3+1,

38+34+32+2+1, 38+34+32+4+3+1, 39+1, 39+2+1, 39+3+1, 39+4+3+1, 39+5+3+1, 39+5+4+3+1, 39+6+1,

39+6+2+1, 39+6+3+1, 39+6+4+3+1, 39+6+5+3+1, 39+6+5+4+3+1, 39+7+6+1, 39+7+6+2+1, 39+7+6+3+1,

39+7+6+4+3+1, 39+7+6+5+3+1, 39+7+6+5+4+3+1, 39+8+7+6+1, 39+8+7+6+2+1, 39+8+7+6+3+1, 15 39+8+7+6+4+3+1, 39+8+7+6+5+3+1, 39+8+7+6+5+4+3+1, 39+9+7+6+1, 39+9+7+6+2+1, 39+9+7+6+3+1,

39+9+7+6+4+3+1, 39+9+7+6+5+3+1, 39+9+7+6+5+4+3+1, 39+10+6+1, 39+10+6+2+1, 39+10+6+3+1,

39+10+6+4+3+1, 39+10+6+5+3+1, 39+10+6+5+4+3+1, 39+11+10+6+1, 39+11+10+6+2+1,

39+11+10+6+3+1, 39+11+10+6+4+3+1, 39+11+10+6+5+3+1, 39+11+10+6+5+4+3+1, 39+12+10+6+1,

39+12+10+6+2+1, 39+12+10+6+3+1, 39+12+10+6+4+3+1, 39+12+10+6+5+3+1, 39+12+10+6+5+4+3+1,

39+13+10+6+1, 39+13+10+6+2+1, 39+13+10+6+3+1, 39+13+10+6+4+3+1, 39+13+10+6+5+3+1,

39+13+10+6+5+4+3+1, 39+14+6+1, 39+14+6+2+1, 39+14+6+3+1, 39+14+6+4+3+1, 39+14+6+5+3+1,

39+14+6+5+4+3+1, 39+15+14+6+1, 39+15+14+6+2+1, 39+15+14+6+3+1, 39+15+14+6+4+3+1,

39+15+14+6+5+3+1, 39+15+14+6+5+4+3+1, 39+16+1, 39+16+2+1, 39+16+3+1, 39+16+4+3+1,

39+16+5+3+1, 39+16+5+4+3+1, 39+17+16+1, 39+17+16+2+1, 39+17+16+3+1, 39+17+16+4+3+1,

39+17+16+5+3+1, 39+17+16+5+4+3+1, 39+18+16+1, 39+18+16+2+1, 39+18+16+3+1, 39+18+16+4+3+1,

39+18+16+5+3+1, 39+18+16+5+4+3+1, 39+19+16+1, 39+19+16+2+1, 39+19+16+3+1, 39+19+16+4+3+1,

39+19+16+5+3+1, 39+19+16+5+4+3+1, 39+20+1, 39+20+3+1, 39+21+20+1, 39+21+20+3+1,

39+22+21+20+1, 39+22+21+20+3+1, 39+23+20+1, 39+23+20+3+1, 39+24+23+20+1, 39+24+23+20+3+1,

39+25+1, 39+25+3+1, 39+26+1, 39+26+3+1, 39+27+1, 39+27+3+1, 39+28+27+1, 39+28+27+3+1,

39+29+27+1, 39+29+27+3+1, 39+30+2+1, 39+30+4+3+1, 39+31+2+1, 39+31+4+3+1, 39+32+2+1,

39+32+4+3+1, 39+33+32+2+1, 39+33+32+4+3+1, 39+34+32+2+1, 39+34+32+4+3+1, 40+1, 40+2+1,

40+3+1, 40+4+3+1, 40+5+3+1, 40+5+4+3+1, 40+6+1, 40+6+2+1, 40+6+3+1, 40+6+4+3+1, 40+6+5+3+1,

40+6+5+4+3+1, 40+7+6+1, 40+7+6+2+1, 40+7+6+3+1, 40+7+6+4+3+1, 40+7+6+5+3+1,

40+7+6+5+4+3+1, 40+8+7+6+1, 40+8+7+6+2+1, 40+8+7+6+3+1, 40+8+7+6+4+3+1, 40+8+7+6+5+3+1,

40+8+7+6+5+4+3+1, 40+9+7+6+1, 40+9+7+6+2+1, 40+9+7+6+3+1, 40+9+7+6+4+3+1, 40+9+7+6+5+3+1,

40+9+7+6+5+4+3+1, 40+10+6+1, 40+10+6+2+1, 40+10+6+3+1, 40+10+6+4+3+1, 40+10+6+5+3+1,

40+10+6+5+4+3+1, 40+11+10+6+1, 40+11+10+6+2+1, 40+11+10+6+3+1, 40+11+10+6+4+3+1,

40+11+10+6+5+3+1, 40+11+10+6+5+4+3+1, 40+12+10+6+1, 40+12+10+6+2+1, 40+12+10+6+3+1,

40+12+10+6+4+3+1, 40+12+10+6+5+3+1, 40+12+10+6+5+4+3+1, 40+13+10+6+1, 40+13+10+6+2+1,

40+13+10+6+3+1, 40+13+10+6+4+3+1, 40+13+10+6+5+3+1, 40+13+10+6+5+4+3+1, 40+14+6+1,

-502015226250 05 Nov 2018

40+14+6+2+1, 40+14+6+3+1, 40+14+6+4+3+1, 40+14+6+5+3+1, 40+14+6+5+4+3+1, 40+15+14+6+1, 40+15+14+6+2+1, 40+15+14+6+3+1, 40+15+14+6+4+3+1, 40+15+14+6+5+3+1, 40+15+14+6+5+4+3+1, 40+16+1, 40+16+2+1, 40+16+3+1, 40+16+4+3+1, 40+16+5+3+1, 40+16+5+4+3+1, 40+17+16+1, 40+17+16+2+1, 40+17+16+3+1, 40+17+16+4+3+1, 40+17+16+5+3+1, 40+17+16+5+4+3+1, 40+18+16+1,

40+18+16+2+1, 40+18+16+3+1, 40+18+16+4+3+1, 40+18+16+5+3+1, 40+18+16+5+4+3+1, 40+19+16+1,

40+19+16+2+1, 40+19+16+3+1, 40+19+16+4+3+1, 40+19+16+5+3+1, 40+19+16+5+4+3+1, 40+20+1, 40+20+3+1, 40+21+20+1, 40+21+20+3+1, 40+22+21+20+1, 40+22+21+20+3+1, 40+23+20+1,

40+23+20+3+1, 40+24+23+20+1, 40+24+23+20+3+1, 40+25+1, 40+25+3+1, 40+26+1, 40+26+3+1, 40+27+1, 40+27+3+1, 40+28+27+1, 40+28+27+3+1, 40+29+27+1, 40+29+27+3+1, 40+30+2+1,

40+30+4+3+1, 40+31+2+1, 40+31+4+3+1, 40+32+2+1, 40+32+4+3+1, 40+33+32+2+1, 40+33+32+4+3+1,

40+34+32+2+1 and 40+34+32+4+3+1.

In the list above, the numbers refer to the disclosures according to their numbering provided hereinabove whereas “+” indicates the dependency from another disclosure. The different individualised disclosures are separated by commas. In other words, “4+3+1” for 15 example refers to disclosure 4) depending on disclosure 3), depending on disclosure 1), i.e.

disclosure “4+3+1” corresponds to disclosure 1) further limited by the features of disclosures 3) and 4). Likewise, “13+10+6+1” refers to disclosure 13) depending mutatis mutandis on disclosures 10) and 6), depending on disclosure 1), i.e. disclosure “13+10+6+1” corresponds to disclosure 1) further limited by the features of 20 disclosures 6) and 10), further limited by the features of disclosure 13).

The compounds of formula I can be manufactured in accordance with the present disclosure using the procedures described hereafter.

PREPARATION OF THE COMPOUNDS OF FORMULA I

Abbreviations:

The following abbreviations are used throughout the specification and the examples:

Ac

AcOH aq.

Boc

BuLi acetyl acetic acid aqueous ieri-butoxycarbonyl n -butyl lithium

- 51 2015226250 05 Nov 2018

cc	column chromatography over silica gel
CDI	1,1’ -carbonyldiimidazole
Cipro	ciprofloxacin
cone.	concentrated
5 Cy	cyclohexyl
DAD	diode array detection
dba	dibenzylideneacetone
DCC	dicyclohexylcarbodiimide
DCE	1,2-dichloroethane
10 DCM	dichloromethane
DIBAH	diisobutylaluminium hydride
DME	1,2-dimethoxyethane
DMF	VVdimethylformamide
DMAP	4-dimethylaminopyridine
15 DMSO	dimethylsulfoxide
dppf	1,1 '-bis(diphenylphosphino)ferrocene
EA	ethyl acetate
EDC	7V-(3-dimethylaminopropyl)-7V'-ethylcarbodiimide hydrochloride
ELSD	evaporative light scattering detector
20 ESI	electron spray ionisation
eq-	equivalent
Et	ethyl
Et₂O	diethyl ether
EtOH	ethanol
25 HATU	<9-(7-azabenzotri azo l -1 -yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate
Hept	heptane
Hex	hexane
HOBT	hydroxybenzotriazole

-522015226250 05 Nov 2018

HPLC iPr

IT

LC

Me

MeCN

MeOH

MS

Ms nBu

NBS

Nf

NMR

Ns org.

Pd/C

PEPPSI™-IPr

PE

Ph

PPTS prep-HPLC

Pyr quant.

Q-phos rt sat.

SK-CC01-A high pressure liquid chromatography zso-propyl internal temperature liquid chromatography methyl acetonitrile methanol mass spectroscopy methylsulfonyl (mesyl) n -butyl

A-bromosuccinimide nonafluorobutanesulfonyl

Nuclear Magnetic Resonance

4-nitrobenzenesulfonyl (nosylate) organic palladium on carbon [l,3-bis(2,6-diisopropylphenyl)imidazol-

2-ylidene](3-chloropyridyl)palladium(II) dichloride petroleum ether phenyl para-toluenesulfonic acid pyridinium salt preparative HPLC pyridine quantitative

1,2,3,4,5-pentaphenyl-1'-(di-ieri-butylphosphino)ferrocene room temperature saturated

2'-(dimethylamino)-2-biphenylyl-palladium(II) chloride dinorbornylphosphine complex

2015226250 05 Nov 2018

- 53 5

S-Phos	2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl
TBAF	tetra-n-butylammonium fluoride
TBDPS	ieri-butyldiphenylsilyl
TBDMS	ierZ-butyldimethylsilyl
TBME	ierZ-butylmethyl ether
tBu	ieri-butyl
TEA	triethylamine
TFA	trifluoroacetic acid
THF	tetrahydrofuran
THP	tetrahydropyranyl
TLC	thin layer chromatography
TMS	trimethylsilyl
TMSE	2-(trimethylsilyl)ethyl
tR	retention time

General reaction techniques'.

General.reaction.technique 1^hydroxamic acidprotectin^^roup removal):

The protecting groups R of the hydroxamic acid ester derivatives (CONHOR) are removed as follows:

When R is THP, (2-methylpropoxy)ethyl, methoxymethyl, tBu, COOtBu or COtBu: by acidic treatment with e.g. TFA or HC1 in an org. solvent such as DCM, dioxane, Et20 or MeOH between 0°C and rt or by treatment with pyridinium para-toluenesulfonate in EtOH between rt and 80°C;

When R is trityl: by treatment with diluted acid such as citric acid or HC1 in an org. solvent such as MeOH or DCM;

When R is benzyl: by hydrogenation using general reaction technique 5;

When R is TMSE: by using fluoride anion sources such as BF3.etherate complex in MeCN at 0°C, TBAF in THF between 0°C and +40°C or HF in MeCN or water between 0°C and +40°C, or using acidic conditions such as AcOH in THF/MeOH or HC1 in MeOH;

-542015226250 05 Nov 2018

- When R is allyl: by treatment with PdfPPtbfl in a solvent such as MeOH in presence of K2CO3 or a scavenger such as dimedone, morpholine or tributyltin hydride;

Further general methods to remove hydroxamic acid protecting groups have been described in T.W. Greene & P.G.M. Wuts, Protecting Groups in Organic Synthesis,

3^rd Ed (1999), 23-147 (Publisher: John Wiley and Sons, Inc., New York, N.Y.).

General reactipn technique.2. (amide .coupling):

The carboxylic acid is reacted with the hydroxylamine derivative in the presence of an activating agent such as DCC, EDC, HOBT, n-propylphosphonic cyclic anhydride, HATU or di-(/V-succinimidyl)-carbonate, in a dry aprotic solvent such as DCM, MeCN or DMF 10 between -20°C and 60°C (see G. Benz in Comprehensive Organic Synthesis, B.M. Trost, I.

Fleming, Eds; Pergamon Press: New York (1991), vol. 6, p. 381). Alternatively, the carboxylic acid can be activated by conversion into its corresponding acid chloride by reaction with oxalyl chloride or thionyl chloride neat or in a solvent like DCM between -20° and 60°C. Further activating agents can be found in R. C. Larock, 15 Comprehensive Organic Transformations. A guide to Functional Group Preparations,

2^nd Edition (1999), section nitriles, carboxylic acids and derivatives, p. 1941-1949 (Wiley-VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto).

General reaction technique.3..(Suzuki .coupling):

The aromatic halide (typically a bromide) is reacted with the required boronic acid 20 derivative or its boronate ester equivalent (e.g. pinacol ester) in the presence of a palladium catalyst and a base such as K2CO3, CS2CO3, K3PO4, tBuONa or tBuOK between 20 and 120°C in a solvent such as toluene, THF, dioxane, DME or DMF, usually in the presence of water (20 to 50%). Examples of typical palladium catalysts are triarylphosphine palladium complexes such as PdfPPtpfl. These catalysts can also be prepared in situ from a 25 common palladium source such as Pd(OAc)2 or Pd2(dba)3 and a ligand such as trialkylphosphines (e.g. PCy3 or PflBufl), dialkylphosphinobiphenyls (e.g. S-Phos) or ferrocenylphosphines (e.g. Q-phos). Alternatively, one can use a commercially available precatalyst based on palladacycle (e.g. SK-CC01-A) or A'-heterocyclic carbene complexes (e.g. PEPPSI™-IPr). The reaction can also be performed by using the corresponding 30 aromatic triflate. Further variations of the reaction are described in Miyaura and Suzuki,

Chem. Rev. (1995), 95, 2457-2483, Beilina et al., Synthesis (2004), 2419-2440, Mauger

- 55 2015226250 05 Nov 2018 and Mignani, Aldrichimica Acta (2006), 39, 17-24, Kantchev et al., Aldrichimica Acta (2006), 39, 97-111, Fu, Acc. Chem. Res. (2008), 41, 1555-1564, and references cited therein.

General....reaction ...technique.. 4....(alkyne₇alkyne....crosscouplings , haloaiyl^ alkyne-haloalkyne.cross coupling):

An alkyne derivative is coupled with a second alkyne or a haloalkyne derivative, using a catalytic amount of a palladium salt, an org. base such as TEA and a catalytic amount of a copper derivative (usually copper iodide) in a solvent such as DMF at a temperature from 20 to 100°C (see Sonogashira, K. in Metal-Catalyzed Reactions, Diederich, F., Stang, P.J., 10 Eds.; Wiley-VCH: New York (1998)). Alternatively, the alkyne-haloalkyne cross coupling reaction can be performed using only a catalytic amount of copper derivative in presence of aqueous hydroxylamine and a base such as piperidine or pyrrolidine (see Chodkiewicz and Cadiot, C. R. Hebd. Seances Acad. Sci. (1955), 241, 1055-1057).

General.reaction technique 5 ..(hydrogenation.ofa .double.bond);

The unsaturated derivative dissolved in a solvent such as MeOH, EA or THF is hydrogenated over a noble metal catalyst such as Pd/C or PtO₂, or over Raney Ni. At the end of the reaction the catalyst is filtered off and the filtrate is evaporated under reduced pressure. Alternatively the reduction can be performed by catalytic transfer hydrogenation using Pd/C and ammonium formate as hydrogen source.

General reaction technique 6 (transformation of an ester into an acid):

When the ester side chain is a linear alkyl, the hydrolysis is usually performed by treatment with an alkali hydroxide such as LiOH, KOH or NaOH in a water-dioxan or water-THF mixture between 0°C and 80°C. When the ester side chain is tBu, the release of the corresponding acid can also be performed in neat TFA or diluted TFA or HCI in an org.

solvent such as ether or THF. When the ester side chain is the allyl group, the reaction is performed in the presence of tetrakis(triphenylphosphine)palladium(0) in the presence of an allyl cation scavenger such as morpholine, dimedone or tributyltin hydride between 0°C and 50°C in a solvent such as THF. When the ester side chain is benzyl, the reaction is performed under hydrogen in the presence of a noble metal catalyst such as Pd/C in a 30 solvent such as MeOH, THF or EA. Further strategies to introduce other acid protecting

-562015226250 05 Nov 2018 groups and general methods to remove them have been described in T.W. Greene &

P.G.M. Wuts, Protecting Groups in Organic Synthesis, 3^rd Ed. (1999), 369-441 (Publisher: John Wiley and Sons, Inc., New York, N.Y.).

General preparation methods'.

Preparation_ofJhe.compounds offormula I:

The compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by a person skilled in the art by routine optimisation procedures.

The sections hereafter describe general methods for preparing compounds of formula I. If not indicated otherwise, the generic groups R¹, M, M^A, M^B, A, U, V, W, R^1A, R^2A, R^3A, R^1Band R^1C are as defined for formula I. General synthetic methods used repeatedly throughout the text below are referenced to and described in the above section entitled “General reaction techniques”. In some instances certain generic groups might be 15 incompatible with the assembly illustrated in the procedures and schemes below and so will require the use of protecting groups. The use of protecting groups is well known in the art (see for example T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis, 3^rd Ed (1999), Wiley-Interscience).

The compounds of formula I can be obtained by deprotecting a compound of formula II

II

-572015226250 05 Nov 2018 wherein R¹ has the same meaning as in formula I and PG represents THP, TMSE, benzyl, trityl, (2-methylpropoxy)ethyl, methoxymethyl, allyl, tBu, COOtBu or COtBu using general reaction technique 1. The reaction can also be performed with racemic material and the (R) enantiomer can be obtained by chiral HPLC separation.

If desired, the compounds of formula I thus obtained may be converted into their salts, and notably into their pharmaceutically acceptable salts using standard methods.

Besides, whenever the compounds of formula I are obtained in the form of mixtures of enantiomers, the enantiomers can be separated using methods known to one skilled in the art, e.g. by formation and separation of diastereomeric salts or by HPLC over a chiral 10 stationary phase such as a Regis Whelk-O1(R,R) (10 pm) column, a Daicel ChiralCel

OD-H (5-10 pm) column, or a Daicel ChiralPak IA (10 pm) or AD-H (5 pm) column. Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH, in the presence or absence of an amine such as TEA or diethylamine) and eluent B (Hex), at a flow rate of 0.8 to 150 mL/min.

Preparation_of the .compoundsof.formula II:

The compounds of formula II can be obtained by:

a) reacting a compound of formula III

III wherein R¹ is as defined in formula I with a compound of formula IV

H₂N-OPG

IV

- 58 2015226250 05 Nov 2018 wherein PG has the same meaning as in formula II using general reaction technique 2 (this reaction can also be performed with racemic compound of formula III and the (R)-enantiomer can then be obtained by chiral HPLC separation of the reaction product), whereby functional groups (e.g. amino or hydroxy) present on R¹ that would 5 be incompatible with the coupling conditions mentioned in general reaction technique 2 can be protected (as carbamates or THP/silyl ethers respectively) before performing said reaction and deprotected after performing said reaction; or

b) reacting a boron derivative of formula V

R^1A

V wherein U, V, R^1A, R^2A and R^3A have the same respective meanings as in formula I, A represents a bond or CH=CH and D¹ and D² represent H, methyl or ethyl or D¹ and D²together represent CH2C(Me)2CH2 or C(Me)2C(Me)2 with a compound of formula VI

VI wherein X^a represents a halogen such as bromine or iodine and PG has the same meaning as in formula II, using general reaction technique 3 (this reaction can also be performed with racemic compound of formula VI and the (R)-enantiomer can then be 15 obtained by chiral HPLC separation of the reaction product); or

-592015226250 05 Nov 2018

c) reacting a compound of formula VII

wherein U, V, R^1A, R^2A and R^3A have the same respective meanings as in formula I, with a compound of formula VI as defined in section b) above wherein X^a represents iodine, using general reaction technique 4 (this reaction can also be performed with racemic compound of formula VI and the (R)-enantiomer can then be obtained by chiral HPLC separation of the reaction product); or

d) reacting a compound of formula VIII

VIII

-60wherein U, V, R^1A, R^2A and R^3A have the same respective meanings as in formula I and

X^b represents iodine or bromine (and preferably iodine), with a compound of formula Via

2015226250 05 Nov 2018

Via

OPG wherein X^a represents ethynyl and PG has the same meaning as in formula II, using general reaction technique 4 (this reaction can also be performed with racemic compound of formula Via and the (R)-enantiomer can then be obtained by chiral HPLC separation of the reaction product); or

e) reacting a compound of formula IX

IX wherein R^1B has the same meaning as in formula I and X^c represents iodine or bromine, with a compound of formula Via as defined in section d) above, using general reaction technique 4 (this reaction can also be performed with racemic compound of formula Via and the (R)-enantiomer can then be obtained by chiral HPLC separation of the reaction product); or

f) reacting a compound of formula X

X

- 61 2015226250 05 Nov 2018 wherein R^1C has the same meaning as in formula I and X^c represents iodine or bromine, with a compound of formula Via as defined in section d) above, using general reaction technique 4 (this reaction can also be performed with racemic compound of formula Via and the (R)-enantiomer can then be obtained by chiral HPLC separation of 5 the reaction product).

Preparation..of.the.synthesis(.intermediates; of.formulae III,..IV, Υ_Λ VL.Via, VII, VIH, IX and X:

Compounds of formula III:

The compounds of formula III can be prepared as summarised in Scheme 1 hereafter.

1-1

I-3

III

I-4

Scheme 1

In Scheme 1, R¹ has the same meaning as in formula I.

The reactions can also be performed with racemic material and the (R)-enantiomer can be obtained by chiral HPLC separation at any step when suitable.

The derivatives of formula 1-3 can be obtained (Scheme 1) by reaction of the pyrrole aldehydes of formula 1-1 with the amine of formula 1-2 using general reaction technique 5. 15 Alternatively, the derivatives of formula 1-3 can be obtained by reacting the derivatives of

-622015226250 05 Nov 2018 formula 1-1 with the derivative of formula 1-2 in a solvent such as MeOH, DCM or DCE (or a mixture of such solvents) in the presence of a reducing agent such as NaBlfi or NaBH(OAc)3; the reductive amination reaction is well known in the art (see for example Abdel-Magid et al., J. Org. Chem. (1996), 61, 3849-3862). The derivatives of formula 1-4 5 can be obtained from the derivatives of formula 1-3 by treatment with CDI in a solvent such as THF in the presence of a base such as NaH; this reaction can be performed at a temperature ranging from 0 to 50°C, and ideally at rt. The compounds of formula 1-4 can be transformed into the compounds of formula III using general reaction technique 6.

The compounds of formula III can also be prepared as summarised in Scheme la hereafter.

1-1

Scheme la

In Scheme la, R¹ has the same meaning as in formula I. The reactions can also be performed with racemic material and the (R)-enantiomer can be obtained by chiral HPLC separation at any step when suitable.

The oxime derivatives of formula 1-5 can be obtained (Scheme la) by reaction of the pyrrole aldehydes of formula 1-1 with hydroxylamine in acetic acid in presence of NaOAc.

The oxime derivatives of formula 1-5 can be reduced into the amine derivatives of

- 63 2015226250 05 Nov 2018 formula 1-6 by treatment with Zn in a solvent such as AcOH. The derivatives of formula 1-7 can be obtained from the derivatives of formula 1-6 by treatment with CDI in a solvent such as THF in the presence of a base such as NaH. This reaction can be performed at a temperature ranging from 0 to 50°C, and ideally at rt. The compounds of formula 1-7 can be transformed into the compounds of formula 1-9 by treatment with the bromide of formula 1-8 in the presence of a base such as NaH and in a solvent such as THF or DMF. The compounds of formula 1-9 can then be transformed into the compounds of formula III using general reaction technique 6.

Compounds of formula IV:

The compounds of formula IV are commercially available (PG = THP, tBu, COOtBu or allyl) or can be prepared according to WO 2010/060785 (PG = (2-methylpropoxy)ethyl) or Marmer and Maerker, J. Org. Chem. (1972), 37, 3520-3523 (PG = COtBu).

Compounds of formula V:

The compounds of formula V wherein A is a bond and D¹ and D² each represent H or 15 (Ci-C2)alkyl are commercially available or can be prepared according to Sieveland et al.,

Organic Process Research & Development (2012), 16, 1121-1130 starting from tri((Ci-C2)alkyl)borate and the corresponding commercially available bromo derivatives (optionally followed by acidic hydrolysis). The compounds of formula V wherein A represents a bond and D¹ and D² together represent CH2C(Me)2CH2 or C(Me)2C(Me)2 are 20 commercially available or can be prepared according to WO 2012/093809, starting from bis(pinacolato)diborane or 5,5-dimethyl-l,3,2-dioxaborinane (both commercially available) with the corresponding commercially available bromo derivatives of formula VIII. The compounds of formula V wherein A is CH=CH and D¹ and D² each represent H are commercially available or can be prepared according to Pemer et al., 25 Biorg. Med. Chem. Lett. (2005), 15, 2803-2807 by reaction of catechol borane on the appropriate alkyne derivatives followed by acidic hydrolysis.

Compounds of formulae VI and Via:

The compounds of formulae VI and Via can be prepared as summarised in Scheme 2 hereafter.

-642015226250 05 Nov 2018

11-1

II-2

Scheme 2

In Scheme 2, X^a represents a halogen (such as iodine or bromine) or ethynyl and PG has the same meaning as in formula II. The reactions can also be performed with racemic material and the (R)-enantiomer can be obtained by chiral HPLC separation at any step when suitable.

The derivatives of formula II-1 can be transformed (Scheme 2) into the carboxylic acid derivatives of formula II-2 using general reaction technique 6 and further reacted with the compounds of formula IV using general reaction technique 2, thus affording the compounds of formula VI (X^a = halogen) or Via (X^a = ethynyl).

- 65 2015226250 05 Nov 2018

Alternatively, the compounds of formula II-2 can be prepared as summarised in Scheme 2a hereafter.

11-3

11-2

Scheme 2a

In Scheme 2a, X^a represents a halogen (such as iodine or bromine) or ethynyl. The reactions can also be performed with racemic material and the (R)-enantiomer can be obtained by chiral HPLC separation at any step when suitable.

The derivatives of formula II-3 can be transformed (Scheme 2a) into the carboxylic acid derivatives of formula II-2 using general reaction technique 6.

Compounds of formula VII:

The compounds of formula VII are commercially available or can be prepared as summarised in Scheme 3 hereafter.

R^1A

VIII (X^b = I) /

—Si-111-1 \

Scheme 3

In Scheme 3, U, V, R^1A, R^2A and R^3A have the same respective meanings as in formula I.

The compounds of formula VIII wherein X^b represents iodine can be reacted (Scheme 3) with trimethylsilylacetylene (III-l) using general reaction technique 4 followed by treatment with TBAF in THF, affording the derivatives of formula VII.

-662015226250 05 Nov 2018

Compounds of formula VIII:

The compounds of formula VIII wherein X^b represents bromine are commercially available or can be prepared by standard methods known to one skilled in the art. The compounds of formula VIII wherein X^b represents iodine can be obtained from the 5 corresponding bromine derivatives by reaction with Nal in the presence of a copper (I) salt and a ligand such as /ra/7s-/V,_iV'-dimethylcyclohexa-l,2-diamine in a solvent such as dioxane at a temperature ranging between rt and 100°C, or in a microwave oven at 150°C.

Compounds of formula IX:

The compounds of formula IX wherein X^c represents iodine can be prepared by iodination 10 of the corresponding compounds wherein X^c would be H with iodine in the presence of an inorganic base such as KOH. The compounds of formula IX wherein X^c represents bromine can be prepared from the corresponding compounds wherein X^c would be H by treatment with NBS in the presence of AgNO3 in a solvent such as acetone or MeCN.

Compounds of formula X:

The compounds of formula X can be prepared as summarised in Scheme 3a hereafter

-672015226250 05 Nov 2018 /

Si—

X-1 X-2

X

Scheme 3a

In Scheme 3a, X^d represents iodine or bromine and W and R^1C have the same respective meanings as in formula X.

The compounds of formula X-1 can be reacted (Scheme 3 a) with trimethylsilylacetylene (III-l) using general reaction technique 4 followed by treatment with TBAF in THF, 5 affording the derivatives of formula X-2. The compounds of formula X wherein X^crepresents iodine can be prepared from the compounds of formula X-2 by treatment with iodine in the presence of an inorganic base such as KOH. The compounds of formula X wherein X^c represents bromine can be prepared from the compounds of formula X-2 by treatment with NBS in the presence of AgNO₃ in a solvent such as acetone or MeCN.

θ Other synthesis intermediates and starting materials:

The compounds of formula 1-1 are commercially available or can be prepared by standard methods known to one skilled in the art.

- 68 2015226250 05 Nov 2018

The compound of formula 1-2 can be prepared in analogy to the methods described in the section entitled “EXAMPLES” hereafter (see Preparations A and B), or by standard methods known to one skilled in the art.

The compounds of formula II-1 wherein X^a represents bromine, iodine or ethynyl can be prepared as summarised in Scheme 4 hereafter.

IV-1

IV-2

11-1

Scheme 4

In Scheme 4, X^a represents a halogen (such as iodine or bromine) or ethynyl. The reactions can also be performed with racemic material and the (R)-enantiomer can be obtained by chiral HPLC separation at any step when suitable.

The derivatives of formula IV-2 can be obtained (Scheme 4) by reaction of the pyrrole aldehydes of formula IV-1 with the amine of formula 1-2 using general reaction technique 5. The derivatives of formula II-l can then be obtained from the derivatives of formula IV-2 by treatment with CDI in the presence of a base such as NaH in a solvent such as THF; this reaction can be performed at a temperature ranging from 0°C to 50°C, and ideally at rt. The compounds of formula IV-3 wherein X^a is iodine can be transformed to the derivatives of formula II-1 wherein X^a is ethynyl using the protocol described for the formation of the compounds of formula VII.

-692015226250 05 Nov 2018

Moreover the compounds of formula II-1 wherein X^a is ethynyl can be obtained from the compounds of formula II-3 wherein X^a is iodine using the protocol described for the formation of the compounds of formula VII.

The compounds of formula II-3 wherein X^a represents bromine, iodine or ethynyl can be prepared as summarised in Scheme 4a hereafter.

Scheme 4a iodine or bromine) or ethynyl. The

In Scheme 4a, X^a represents a halogen (such as reactions can also be performed with racemic material and the (R)-enantiomer can be obtained by chiral HPLC separation at any step when suitable.

The oxime derivatives of formula IV-3 can be obtained (Scheme 4a) by reaction of the 10 pyrrole aldehydes of formula IV-1 with hydroxylamine in AcOH in the presence of

NaOAc. The oxime derivatives of formula IV-3 can be reduced to the amine derivatives of formula IV-4 by treatment with Zn in a solvent such as AcOH. The derivatives of formula IV-5 can be obtained from the derivatives of formula IV-4 by treatment with CDI in a solvent such as THF in the presence of a base such as NaH. This reaction can be 15 performed at a temperature ranging from 0 to 50°C, and ideally at rt. The compounds of formula IV-5 can then be transformed into the compounds of formula II-3 by treatment

-702015226250 05 Nov 2018 with the bromide of formula 1-8 in the presence of a base such as NaH and in a solvent such as THF or DMF.

The compounds of formula IV-1 are commercially available or can be prepared by standard methods known to one skilled in the art.

The compounds of formula X-1 are commercially available or can be prepared by standard methods known to one skilled in the art.

Particular embodiments of the invention are described in the following Examples, which serve to illustrate the invention in more detail without limiting its scope in any way.

EXAMPLES

All temperatures are stated in °C. Unless otherwise indicated, the reactions take place at rt.

Analytical TLC characterisations were performed with 0.2 mm plates: Merck, Silica gel 60 F254. Elution is performed with EA, Hept, DCM, MeOH or mixtures thereof. Detection was done with UV or with a solution of KMnO4 (3 g), K2CO3 (20 g), 5% NaOH (3 mL) and H2O (300 mL) with subsequent heating.

CCs were performed using Brunschwig 60A silica gel (0.032-0.63 mm) or using an ISCO CombiFlash system and prepacked S1O2 cartridges, elution being carried out with either Hept-EA or DCM-MeOH mixtures with an appropriate gradient. When the compounds contained an acid function, 1% of AcOH was added to the eluent(s). When the compounds contained a basic function, 25% aq. NH4OH was added to the eluents.

The compounds were characterized by 'H-NMR (300 MHz, Varian Oxford; 400 MHz, Bruker Avance 400 or 500 MHz, Bruker Avance 500 Cryoprobe). Chemical shifts δ are given in ppm relative to the solvent used; multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, hex = hexet, hep = heptet, m = multiplet, br. = broad; coupling constants J are given in Hz. Alternatively compounds were characterized by LC-MS (Sciex

API 2000 with Agilent 1100 Binary Pump with DAD and ELSD or an Agilent quadrupole MS 6140 with Agilent 1200 Binary Pump, DAD and ELSD); by TLC (TLC plates from Merck, Silica gel 60 F254); or by melting point.

- 71 2015226250 05 Nov 2018

The analytical LC-MS data have been obtained using the following respective conditions:

o Column: Zorbax SB-Aq, 30.5 pm, 4.6 x 50 mm;

o Injection volume: 1 pL;

o Column oven temperature: 40°C;

o Detection: UV 210 nm, ELSD and MS;

o MS ionization mode: ESI+;

o Eluents: A: H₂O + 0.04% TFA; and B: MeCN;

o Flow rate: 40.5 mL/min;

o Gradient: 5% B to 95% B (0.0 min - 1.0 min), 95% B (1.0 min - 1.45 min).

The number of decimals given for the corresponding [M+H⁺] peak(s) of each tested compound depends upon the accuracy of the LC-MS device actually used.

The prep-HPLC purifications were performed on a Gilson HPLC system, equipped with a Gilson 215 autosampler, Gilson 333/334 pumps, Dionex MSQ Plus detector system, and a Dionex UVD340U (or Dionex DAD-3000) UV detector, using the following respective 15 conditions:

• Method 1:

o Column: Waters XBridge C18, 10 pm, 30 * 75 mm;

o Flow rate: 75 mL/min;

o Eluents: A: H₂O + 0.5% HCOOH; B: MeCN;

o Gradient: 90% A to 5% A (0.0 min - 4.0 min), 5% A (4.0 min - 6.0 min).

• Method 2:

o Column: Waters Atlantis T3 OBD, 10 pm, 30 ^x 75 mm;

o Flow rate: 75 mL/min;

o Eluents: A: H₂O + 0.1% HCOOH; B: MeCN + 0.1% HCOOH;

o Gradient: 90% A to 5% A (0.0 min - 4.0 min), 5% A (4.0 min - 6.0 min).

• Method 3:

o Column: Waters XBridge C18, 10 pm, 30*75 mm;

o Flow rate: 75 mL/min;

o Eluents: A: H₂O + 0.5% NH4OH solution (25%); B: MeCN;

Gradient: 90% A to 5% A (0.0 min - 4.0 min), 5% A (4.0 min - 6.0 min).

-722015226250 05 Nov 2018

Besides, semi-preparative chiral HPLCs were performed using the conditions herafter.

Semi-preparative chiral HPLC Method A:

The semi-preparative chiral HPLC is performed on a Daicel ChiralPak ASV column (250 x 110 mm, 20 μΜ) using the eluent mixture, flow rate and detection conditions 5 indicated between brackets in the corresponding experimental protocol. The retention times are obtained by elution of analytical samples on a Daicel ChiralPak AS-H column (250 x 4.6 mm, 5 μΜ) using the same eluent mixture with the flow rate indicated between brackets in the corresponding experimental protocol.

Semi-preparative chiral HPLC Method B:

The semi-preparative chiral HPLC is performed on a Daicel ChiralPak IA column (20 x 250 mm; 5 μΜ) using the eluent mixture, flow rate and detection conditions indicated between brackets in the corresponding experimental protocol. The retention times are obtained by elution of analytical samples on a Daicel ChiralPak IA column (4.6 x 250 mm; 5 μΜ) using the same eluent mixture with the flow rate indicated between 15 brackets in the corresponding experimental protocol.

Semi-preparative chiral HPLC Method C:

The semi-preparative chiral HPLC is performed on a Daicel ChiralPak AY-H column (20 x 250 mm, 5 μΜ) using the eluent mixture, flow rate and detection conditions indicated between brackets in the corresponding experimental protocol. The retention 20 times are obtained by elution of analytical samples on a Daicel ChiralPak AY-H column (4.6 x 250 mm, 5 μΜ) using the same eluent mixture with the flow rate indicated between brackets in the corresponding experimental protocol.

Semi-preparative chiral HPLC Method D:

The semi-preparative chiral HPLC is performed on a Daicel ChiralCel OD-H column 25 (20 x 250 mm; 5 μΜ) using the eluent mixture, flow rate and detection conditions indicated between brackets in the corresponding experimental protocol. The retention times are obtained by elution of analytical samples on a Daicel ChiralCel OD-H column (4.6 x 250 mm; 5 μΜ) using the same eluent mixture with the flow rate indicated between brackets in the corresponding experimental protocol.

- 73 2015226250 05 Nov 2018

Procedures:

Procedure A:

A mixture of the bromo derivative (1.63 mmol), the phenylboronic acid or boronate ester derivative (1.8 mmol), K2CO3 (0.34 g; 2.4 mmol) and Pd(PPh3)4 (0.19 g; 0.16 mmol) is 5 flushed with nitrogen for 15 min. Dioxane (6 mL) and water (1.5 mL) are added and the mixture is refluxed for 1 h. After cooling, water (15 mL) and EA (20 mL) are added and the two layers are separated. The aq. layer is extracted with EA (2 x 20 mL) and the combined org. layers are washed with brine, dried over MgSCL and concentrated to dryness. The residue is then purified by CC (Hept-EA).

Procedure B:

To a solution of the THP-protected hydroxamic acid derivative (0.84 mmol) in dioxane (3.6 mL) and water (0.8 mL) is added PPTS (0.12 g; 0.48 mmol). The reaction mixture is stirred at 70°C for 2 h. The reaction is cooled to rt and concentrated to dryness. The residue is then purified by CC (DCM-MeOH).

Procedure C:

Cui (0.218 g; 1.14 mmol), PdCh(PPh3)2 (0.401 g; 0.57 mmol), (trimethylsilyl)ethynyl acetylene (5.71 mmol) and the iodo derivative (5.71 mmol) are introduced in a two-necked round flask. The atmosphere is flushed with nitrogen during 30 min, then degassed THF (50 mL) and degassed TEA (2 mL; 14.3 mmol) are added. The suspension is stirred under 20 nitrogen atmosphere at 50°C for 45 min. After concentration to dryness, the residue is then purified by CC (Hept-EA).

Procedure D:

To the THP-protected hydroxamic acid derivative (0.02 mmol) in EtOH (3 mL) is added PPTS (0.025 g; 0.03 mmol). The mixture is stirred at 80°C for 2 h, cooled to rt and directly 25 purified by CC (DCM-MeOH) or by prep-HPLC using a suitable method.

Procedure E:

Cui (0.2 mmol), PdCh(PPh3)2 (0.1 mmol), the terminal alkyne derivative (1 mmol) and the iodo derivative (1.5 mmol) are introduced in a two-necked round flask. The atmosphere is flushed with nitrogen during 30 min, then degassed THF (5 mL) and degassed TEA

-742015226250 05 Nov 2018 (2.5 mmol) are added. The suspension is stirred under nitrogen atmosphere at 50°C for 45 min. After concentration to dryness, the residue is then purified by CC (Hept-EA).

Procedure F:

Cui (0.2 mmol), PdCh(PPh3)2 (0.1 mmol), the iodo derivative (1 mmol) and the terminal alkyne derivative (1.5 mmol) are introduced in a two-necked round flask. The atmosphere is flushed with nitrogen during 30 min, then degassed THF (5 mL) and degassed TEA (2.5 mmol) are added. The suspension is stirred under nitrogen atmosphere at 50°C for 45 min. After concentration to dryness, the residue is then purified by CC (Hept-EA).

Procedure G_:

Cui (0.2 mmol), PdCh(PPh3)2 (0.1 mmol), the terminal alkyne derivative (1 mmol) and the halo-alkyne derivative (1.5 mmol) are introduced in a two-necked round flask. The atmosphere is flushed with nitrogen during 30 min, then degassed THF (5 mL) and degassed TEA (2.5 mmol) are added. The suspension is stirred under nitrogen atmosphere at 50°C for 45 min. After concentration to dryness, the residue is then purified by CC (Hept-EA).

Procedure H:

To the THP-protected hydroxamic acid derivative (0.070 g, 0.119 mmol) in H2O (0.745 mL, 41.4 mmol) was added TFA (0.357 mL, 4.62 mmol) .After one hour stirring at rt, the mixture was directly purified by prep-HPLC using a suitable method.

Procedure I:

A solution of the THP-protected hydroxamic acid derivative (0.070 g, 0.119 mmol) in 4Λ7 HCI in dioxane (1 mL) was stirred 10 min at rt. The mixture was directly purified by prep-HPLC using a suitable method.

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PREPARATIONS:

Preparation A: (/JAj-toT-butyl 4-amino-2-methyl-2-(methylsulfonyl)butanoate:

A.i. (RS)-tert-butyl 2-(methylsulfonyl)propanoate:

To a suspension of sodium methanesulfinate (100 g; 929 mmol) in tBuOH (350 mL) was added ieri-butyl-2-bromopropionate (150 mL; 877 mmol). The reaction mixture was stirred at 90°C for 24 h under nitrogen atmosphere, then cooled to rt and concentrated to dryness. The residue was partitioned between water (750 mL) and EA (600 mL). The aq. layer was extracted with EA (2 x 500 mL) and the combined org. layers were washed with brine (350 mL), dried over MgSCL, filtered and concentrated to dryness to afford the title 10 compound as a white yellow solid (175 g, 96% yield).

Ή NMR (i/₆-DMSO) δ: 4.24 (q, J = 7.2 Hz, IH); 3.11 (s, 3H); 1.45 (s, 9H); 1.40 (d, J = 7.2 Hz, 3H).

A. ii. (RS)-tert-butyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate:

To an ice-chilled suspension of intermediate A.i (130 g; 626 mmol) in DMF (750 mL) was added portionwise NaH (60% in mineral oil; 32.1 g; 802 mmol) for 1.5 h, keeping the temperature below 7°C. The mixture was stirred at 0°C for 1.5 h, allowed to reach rt and stirred at rt for 0.5 h .The mixture was cooled down to 12°C with an ice bath and

1,2-dibromoethane (166 mL; 1.9 mol) was then added dropwise, keeping the temperature below 22°C. The reaction mixture was stirred at rt for 2 h. The mixture was poured into 20 cold water (1 L) and Et2O (1 L) and the aq. layer was extracted with Et2O (2 x 750 mL).

The org. layer was washed with cold water (2 x 500 mL). The combined org. layers were washed with brine (750 mL), dried over MgSCU, filtered and concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a pale yellowish oil (116.8 g; 59% yield).

Ή NMR (Λ-DMSO) δ: 3.63-3.71 (m, IH); 3.37-3.45 (m, IH); 3.12 (s, 3H); 2.62-2.72 (m, IH); 2.33-2.43 (m, IH); 1.49 (s, 3H); 1.46 (s, 9H).

A. iii. (RS)-tert-butyl 4-azido-2-methyl-2-(methylsulfonyl)butanoate:

To a solution of intermediate A.ii (70.3 g; 223 mmol) in DMF (400 mL) was added sodium azide (54.6 g; 831 mmol). The reaction was stirred at 80°C overnight. The mixture was

-762015226250 05 Nov 2018 cooled to rt and water (500 mL) and EA (500 mL) were added. The aq. layer was extracted with EA (2 x 500 mL) and the org. layer was washed with water (2 x 500 mL). The combined org. layers were washed with brine (600 mL), dried over MgSCU, filtered and concentrated to dryness. The residue was triturated in Hept, filtered and washed with Hept 5 to afford the title compound as a white solid (59.6 g; 96% yield).

Ή NMR (rL-DMSO) δ: 3.60-3.66 (m, IH); 3.29-3.35 (overlapped m, IH); 3.11 (s, 3H);

2.43-2.49 (m, IH); 1.96-2.04 (m, IH); 1.46 (s, 9H); 1.44 (s, 3H).

MS (ESI, m/z): 278.95 [M+H⁺] for C10H19N3O4S; t_R = 0.80 min.

A. iv. (RS)-tert-butyl 4-amino-2-methyl-2-(methylsulfonyl)butanoate:

A solution of intermediate A.iii (45 g; 162 mmol) in a mixture of tBuOH/EA (1/1, 900 mL) was treated with 10% Pd/C (2.3 g). The suspension was stirred at rt under hydrogen for 4 h. Then 10% Pd/C (0.5 g) was added to the suspension and the reaction was stirred under hydrogen for 2 days. The catalyst was filtered off and the filtrate concentrated to dryness to afford the crude material which crystallized on standing (grey solid; 40.6 g; 99% yield).

Ή NMR (rL-DMSO) δ: 3.06 (s, 3H); 2.63-2.75 (m, IH); 2.40-2.53 (overlapped m, IH);

2.16-2.28 (m, IH); 1.74-1.85 (m, IH); 1.44 (s, 9H); 1.40 (s, 3H).

MS (ESI, m/z): 252.03 [M+H⁺] for C10H21NO4S; t_R = 0.45 min.

Preparation B: (R)-toT-butyl 4-amino-2-methyl-2-(methylsulfonyl)butanoate:

B. i. (R)-tert-butyl 4-azido-2-methyl-2-(methylsulfonyl)butanoate:

Intermediate A.iii (184 g) was separated by semi-preparative chiral HPLC Method A (Hept-iPrOH 4-1; flow rate: 570 mL/min; UV detection at 235 nM); the respective retention times were 8.3 and 10.7 min. The title (R)-enantiomer, identified as the second eluting compound, was obtained as a light orange oil (90.7 g).

Ή NMR (rL-DMSO) δ: 3.60-3.66 (m, IH); 3.29-3.35 (overlapped m, IH); 3.11 (s, 3H); 25 2.43-2.50 (overlapped m, IH); 1.97-2.04 (m, IH); 1.46 (s, 9H); 1.44 (s, 3H).

B. ii. (R)-tert-butyl 4-amino-2-methyl-2-(methylsulfonyl)butanoate:

Starting from intermediate B.i (45 g; 162 mmol) and proceeding in analogy to Preparation A, step A.iv, the title compound was obtained as grey solid (40.6 g; 99% yield).

-772015226250 05 Nov 2018

Ή NMR (ί/6-DMSO) δ: 3.06 (s, 3H); 2.63-2.75 (m, 11H); 2.40-2.53 (overlapped m, IH);

2.16-2.28 (m, IH); 1.74-1.85 (m, IH); 1.44 (s, 9H); 1.40 (s, 3H).

MS (ESI, m/z): 252.03 [M+H⁺] for C10H21NO4S; t_R= 0.45 min.

Preparation C: (2/?)-4-(6-bromo-3-oxo-lZ/-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)5 2-methyl-2-(methylsulfonyl)-N-(((/?5)-tetrahydro-2Zf-pyran-2-yl)oxy)butanamide:

C.i. (R)-tert-butyl 4-(((4-bromo-lH-pyrrol-2-yl)methyl)amino)-2-methyl-

2-(methylsulfonyl)butanoate:

To a solution of 4-bromo-17/-pyrrole-2-carbaldehyde (4.6 g; 26.3 mmol, commercial) in dry THF (90 mL) were added 3A molecular sieves (5.5 g) and the compound of

Preparation B (6.9 g; 27.6 mmol). The reaction mixture was stirred at rt for 2.5 h, diluted with dry MeOH (25 mL) and cooled to 0°C. NaBH4 (1.0 g; 26.3 mmol) was added portionwise and the reaction was stirred at 0°C for 1.5 h. The mixture was quenched with water (50 mL). The volatiles were removed in vacuo and the residue was partitioned between DCM (100 mL) and sat. aq. NaHCO3 (50 mL). The mixture was filtered and the 15 phases were separated. The aq. phase was extracted with DCM (100 mL). The combined org. layers were dried over MgSO4 and filtered. The filtrate was concentrated to dryness.

After purification by CC (DCM-EA-MeOH), the title compound was obtained as an orange gum (9.0 g, 84% yield).

Ή NMR (ί/ή-DMSO) δ: 10.78-10.95 (br. s, IH); 6.71-6.74 (m, IH); 5.91-5.93 (m, IH); 20 3.50-3.60 (m, 2H); 3.06 (s, 3H); 2.53-2.59 (m, IH); 2.35-2.41 (m, IH); 2.25-2.32 (m, IH);

1.93-1.98 (br. s, IH); 1.76-1.84 (m, IH); 1.40 (s, 9H); 1.38 (s, 3H).

MS (ESI, m/z): 410.89 [M+H⁺] for Cisfts^CLBrS; t_R = 0.63 min.

C. ii. (R)-tert-butyl 4-(6-bromo-3-oxo-lH-pyrrolo[1,2-c]imidazol-2(3H)-yl)-2-methyl-

2-(methylsulfonyl) butanoate:

To a solution of intermediate C.i (9.0 g; 22.1 mmol) in THF (80 mL) was added CDI (4.3 g; 26.5 mmol) and NaH (60% in mineral oil, 0.123 g; 3.1 mmol). The reaction was stirred at rt for 30 min. The reaction was quenched with water (70 mL) and sat. NH4CI (25 mL). EA (75 mL) was added and the two phases were separated. The aq. phase was extracted with EA (75 mL). The combined org. layers were washed with brine (125 mL), dried over MgSCU and filtered. The filtrate was concentrated to dryness. The residue was

- 78 2015226250 05 Nov 2018 triturated in Et20, filtered and washed with Et20 to afford the title compound as a light beige solid (5.2 g; 54% yield).

Ή NMR (rts-DMSO) δ: 7.37 (s, IH); 6.24 (d, J =1.0 Hz, IH); 4.36-4.48 (m, 2H); 3.52-3.61 (m, IH); 3.41-3.51 (m, IH); 3.13 (s, 3H); 2.50-2.60 (overlapped m, IH);

2.00-2.08 (m, IH); 1.53 (s, 3H); 1.35 (s, 9H).

MS (ESI, m/z): 434.87 [M+H⁺] for Ci6H₂3N₂O₅BrS; t_R = 0.87 min.

C. Hi. (R)-4-(6-bromo-3-oxo-lH-pyrrolo[1,2-c]imidazol-2(3H)-yl)-2-methyl-

2-(methylsulfonyl)butanoic acid:

A solution of intermediate C.ii (5.2 g; 11.9 mmol) in dioxane (45 mL) and water (23 mL) was treated dropwise with cone, sulfuric acid (7.4 mL; 135 mmol). The mixture was stirred at 70°C for 5 h. The reaction mixture was cooled to rt, diluted in cold water (90 mL) and extracted with DCM-MeOH (9-1; 2 x 130 mL). The combined org. layers were dried over MgSCU and filtered. The filtrate was concentrated to dryness. The residue was triturated in DCM, filtered and washed with DCM to afford the title compound as a yellow solid (3.4 g,

76 % yield).

Ή NMR (i/₆-DMSO) δ: 13.46-14.16 (br. s, IH); 7.35 (d, J = 0.8 Hz, IH); 6.22 (d, J = 0.8 Hz, IH); 4.35-4.49 (m, 2H); 3.55-3.65 (m, IH); 3.43-3.53 (m, IH); 3.13 (s, 3H); 2.51-2.59 (overlapped m, IH); 2.00-2.10 (m, IH); 1.54 (s, 3H).

MS (ESI, m/z): 380.82 [M+H⁺] for CnHis^OsBrS; t_R = 0.67 min.

C.iv. (2R)-4-(6-bromo-3-oxo-lH-pyrrolo[l,2-c]imidazol-2(3H)-yl)-2-methyl-

2-(methylsulfonyl)-N-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide:

To a solution of intermediate C.iii (3.4 g; 8.1 mmol) in DMF (50 mL) were successively added EDC (3.4 g; 17.8 mmol), HOBT.H₂O (2.2 g; 16.1 mmol), TEA (3.39 mL, 24.4 mmol) and NH2-OTHP (1.428 g; 12.2 mmol) .The reaction was stirred at 50°C for 2 h under nitrogen. The mixture was cooled to rt, EA (400 mL) and sat. aq. NaHC'Ch (400 mL) were added. The phases were separated and the aq. layer was extracted with EA (400 mL).

The combined org. layers were washed successively with sat. aq. NaHC'Ch (400 mL), water (400 mL) and brine (400 mL), dried over MgSCh and filtered. The filtrate was concentrated to dryness. After purification by CC (Hept-EA), the title compound was 30 obtained as a white solid (3.4 g; 89% yield).

-792015226250 05 Nov 2018 ^!H NMR (%-DMSO) (mixture of stereoisomers) δ: 11.34-11.41 (br. s, 0.5H); 11.29-11.34 (br. s, 0.5H); 7.32 (s, 0.5H); 7.30 (s, 0.5H); 6.19-6.22 (m, 1H); 4.84-4.87 (m, 0.5H); 4.43-4.45 (overlapped m, 0.5H); 4.40-4.43 (overlapped m, 2H); 3.98-4.05 (m, 0.5H); 3.92-3.98 (m, 0.5H); 3.42-3.55 (overlapped m, 3H); 3.06 (s, 1.5H); 3.03 (s, 1.5H);

2.55-2.70 (overlapped m, 1H); 1.92-2.01 (m, 1H); 1.61-1.70 (m, 2H); 1.56 (s, 1.5H);

1.54 (s, 1.5H); 1.43-1.52 (overlapped m, 4H).

MS (ESI, m/z): 477.89 [M+H⁺] for CivI^NsOeSBr; t_R = 0.77 min.

Preparation D: (2/?5)-4-(6-bromo-3-oxo-lZ/-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)-

2-methyl-2-(methylsulfonyl)-V-(((/?A’)-tetrahydro-2//-pyran-2-yl)oxy)butanamide:

Starting from the compound of Preparation A (3.05 g; 20.1 mmol) and proceeding in analogy to Preparation C, steps C.i to C.iv (yields: reductive amination: 47%; cyclisation: 52%; acid formation: 71%; amide coupling with THPO-NEfl: 53%), the title compound was obtained as a white solid (1.7 g).

'H NMR (%-DMSO) (mixture of stereoisomers) δ: 11.38 (br. s, 0.5H); Π.32 (br. s, 0.5H);

7.32 (s, 0.5H); 7.30 (s, 0.5H); 6.19-6.22 (m, 1H); 4.84-4.87 (m, 0.5H);

4.43-4.45 (overlapped m, 0.5H); 4.40-4.43 (overlapped m, 2H); 3.98-4.05 (m, 0.5H); 3.92-3.98 (m, 0.5H); 3.42-3.55 (overlapped m, 3H); 3.06 (s, 1.5H); 3.03 (s, 1.5H);

I. 54 (s, 1.5H); 1.43-1.52 (overlapped m, 4H).

MS (ESI, m/z): 479.85 [M+H⁺] for Ci₇H₂4N₃O6SBr; t_R = 0.77 min.

Preparation E: (2/?)-4-(6-iodo-3-oxo-lZ/-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)-2-methyl-

2-(methylsulfonyl)-V-(((/?A)-tetrahydro-2//-pyran-2-yl)oxy)butanamide:

Starting from 4-iodo-17f-pyrrole-2-carbaldehyde (15 g; 67.9 mmol; commercial) and proceeding in analogy to Preparation C, steps C.i to C.iv (yields: reductive 25 amination: 85%; cyclisation: 67%; acid formation: 74%; amide coupling with THPO-NH₂: 51%), the title compound was obtained as a white solid (7.6 g).

'H NMR (%-DMSO) (mixture of stereoisomers) δ: 11.34-11.46 (br. s, 0.5H);

II. 28-11.34 (br. s, 0.5H); 7.29 (d, J = 0.7 Hz, 0.5H); 7.28 (d, J = 0.7 Hz, 0.5H); 6.20-6.23 (m, 1H); 4.83-4.87 (m, 0.5H); 4.35-4.48 (m, 2.5H); 3.99-4.08 (m, 0.5H);

3.90-3.98 (m, 0.5H); 3.38-3.56 (m, 3H); 3.06 (s, 1.5H); 3.03 (s, 1.5H); 2.56-2.72 (m, 1H);

-802015226250 05 Nov 2018

l. 92-2.00 (m, 1H); 1.60-1.68 (m, 2H); 1.55 (s, 1.5H); 1.54 (s, 1.5H); 1.41-1.54 (overlapped m, 4H).

MS (ESI, m/z): 525.84 [M+H⁺] for C17H24N3O6IS; t_R = 0.78 min.

Preparation F: (22tS)-4-(6-iodo-3-oxo-lH-pyrrolo[l,2-c]imidazol-2(3.H)-yl)-2-methyl5 2-(methylsulfonyl)-V-(((/?5')-tetrahydro-2//-pyran-2-yl)oxy)butanamide:

Starting from 4-iodo-177-pyrrole-2-carbaldehyde (4.7 g; 21.2 mmol; commercial) and the compound of Preparation A (5.6 g; 22.2 mmol) and proceeding in analogy to Preparation C, steps C.i to C.iv (yields: reductive amination: 45%; cyclisation: 81%; acid formation: 78%; amide coupling with ΤΗΡΟ-ΝΗ₂: 71%), the title compound was obtained 10 as a white foam (2.3 g).

H NMR (<A-DMSO) (mixture of stereoisomers) δ: 11.26 (br. s, 1H); 7.26-7.30 (m, 1H); 6.20-6.23 (m, 1H); 4.83-4.87 (m, 0.5H); 4.38-4.44 (m, 2.5H); 3.88-4.06 (m, 1H);

3.36-3.56 (m, 3H); 3.05 (s, 1.5H); 3.02 (s, 1.5H); 2.54-2.68 (m, 1H); 1.90-2.03 (m, 1H); 1.57-1.69 (m, 2H); 1.56 (s, 1.5H); 1.54 (s, 1.5H); 1.38-1.51 (overlapped m, 4H).

MS (ESI, m/z): 525.90 [M+H⁺] for C17H24N3O6IS; t_R = 0.79 min.

Preparation G: (/?5)-4-(6-ethynyl-3-oxo-lZ/-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)-

2-methyl-2-(methylsulfonyl)-V-(((/?A)-tetrahydro-2//-pyran-2-yl)oxy)butanamide:

G. i. (RS)-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-((trimethylsilyl)ethynyl)lH-pyrrolo[l,2-c]imidazol-2(3H)-yl)-N-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide:

Cui (0.126 g; 0.662 mmol) and PdCh(PPh3)2 (0.236 g; 0.336 mmol) were introduced in a two-necked round-bottom flask. After flushing with nitrogen for 30 min, a solution of the compound of Preparation F (1.73 g; 3.29 mmol) in degassed THF (3 mL) was added followed with trimethylsilylacetylene (0.516 mL, 3.62 mmol). Degassed TEA (1.15 mL, 0.73 mmol) was added and the reaction proceeded at 50°C for 2 h. The mixture was 25 concentrated to dryness and the residue was purified by CC (Hept-EA) to afford the title compound as a yellow foam (1.54 g, 94% yield).

^!H NMR (<A-DMSO) (mixture of stereoisomers) δ: 11.25-11.40 (m, 1H); 7.29-7.39 (m, 1H); 6.12-6.21 (m, 1H); 4.80-4.91 (m, 0.5H); 4.45-4.53 (m, 0.5H); 4.32-4.44 (m, 2H); 3.96-4.05 (m, 1H); 3.34-3.51 (m, 3H); 3.06 (s, 1.5H); 3.03 (s, 1.5H); 2.53-2.72 (m, 1H);

- 81 2015226250 05 Nov 2018

1.88-2.04 (m, 1H); 1.60-1.68 (overlapped m, 2H); 1.56 (s, 1.5H); 1.54 (s, 1.5H);

I. 44-1.54 (overlapped m, 4H); 0.17 (s, 9H).

MS (ESI, m/z): 496.01 [M+H⁺] for C₂2H33N₃O6SSi; t_R = 0.90 min.

G. ii. (RS)-4-(6-ethynyl-3-oxo-lH-pyrrolo[1,2-c]imidazol-2(3H)-yl)-2-methyl-

2-(methylsulfonyl)-N-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide:

To a solution of intermediate G.i (1.53 g; 3.09 mmol) in MeOH (10 mL) was added K2CO3 (0.77 g; 5.56 mmol). The mixture was stirred at rt for 1 h. The reaction was diluted with DCM-MeOH 9-1 (100 mL) and water (50 mL). The aq. layer was extracted three times with DCM-MeOH 9-1 (3 x 75 mL). The combined org. layers were dried over MgSO4, 10 filtered and the filtrate concentrated to dryness. The residue was purified by CC (DCM-MeOH) to afford the title compound as a yellow foam (1.09 g; 83% yield).

'H NMR (i/o-DMSO) (mixture of stereoisomers) δ: 11.32-11.36 (br. s, 0.5H);

II. 28-11.32 (br. s, 0.5H); 7.35-7.40 (m, 1H); 6.16-6.20 (m, 1H); 4.83-4.88 (m, 0.5H);

4.46-4.52 (m, 0.5H) 4.38-4.44 (m, 2H); 3.89-4.08 (overlapped m, 1H); 3.94 (s, 1H);

3.38-3.54 (m, 3H); 3.05 (s, 1.5H); 3.03 (s, 1.5H); 2.40-2.50 (overlapped m, 1H);

l. 86-2.04 (m, 1H); 1.61-1.69 (m, 2H); 1.56 (s, 1.5H); 1.54 (s, 1.5H); 1.42-1.52 (overlapped m, 4H).

MS (ESI, m/z): 423.98 [M+H⁺] for C19H25N3O6S; t_R = 0.74 min.

Preparation H: (/?)-4-(6-ethynyl-3-oxo-lZZ-pyrrolo[l,2-c]imidazol-2(3ZZ)-yl)20 2-methyl-2-(methylsulfonyl)-V-(((/?5)-tetrahydro-2//-pyran-2-yl)oxy)butanamide:

H. i. (R)-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-((trimethylsilyl)ethynyl)- lH-pyrrolo[l,2-c]imidazol-2(3H)-yl)-N-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide:

Starting from the compound of Preparation E (3.0 g; 5.7 mmol) and proceeding in analogy to Preparation G, step G.i, the title compound was obtained as a brown foam (2.52 g; 89% 25 yield).

^!H NMR (i/^-DMSO) (mixture of stereoisomers) δ: 11.36-11.38 (br. s, 0.5H); 11.31-11.34 (br. s, 0.5H); 7.38 (s, 0.5H); 7.37 (s, 0.5H); 6.17-6.22 (m, 1H); 4.84-4.88 (m, 0.5H); 4.44-4.48 (m, 0.5H); 4.37-4.44 (m, 2H); 4.01-4.06 (m, 0.5H); 3.93-4.00 (m, 0.5H);

3.36-3.55 (m, 3H); 3.06 (s, 1.5H); 3.03 (s, 1.5H); 2.55-2.68 (m, 1H); 1.94-2.00 (m, 1H);

2015226250 05 Nov 2018

I. 60-1.67 (m, 2H); 1.55 (s, 1.5H); 1.54 (s, 1.5H); 1.45-1.52 (overlapped m, 4H); 0.20 (s, 9H).

MS (ESI, m/z): 496.01 [M+H⁺] for C24H34N₂O₅SSi; t_R = 0.90 min.

H. ii. (R)-4-(6-ethynyl-3-oxo-lH-pyrrolo[l,2-c]imidazol-2(3H)-yl)-2-methyl-

2-(methylsulfonyl)-N-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide:

To a solution of intermediate H.i (2.5 g; 5.4 mmol) in THF (11 mL) was added TBAF (1ΛΤ in THF; 5.2 mL). The mixture was stirred at rt for 20 min. The mixture was concentrated to dryness and the residue was purified by CC (DCM-MeOH) to afford the title compound as a pale brown foam (2.02 g; 94% yield).

'H NMR (ί/ά-DMSO) (mixture of stereoisomers) δ: 11.35-11.40 (br. s, 0.5H);

II. 29-11.34 (br. s, 0.5H); 7.39 (d, J = 0.5 Hz, 0.5H); 7.38 (d, J = 0.5 Hz, 0.5H);

6.16-6.21 (m, IH); 4.84-4.87 (m, 0.5H); 4.45-4.48 (m, 0.5H); 4.38-4.43 (m, 2H); 4.00-4.06 (overlapped m, 0.5H); 3.97 (s, IH); 3.91-3.97 (overlapped m, 0.5H);

3.45-3.55 (m, 1.5H); 3.38-3.45 (m, 1.5H); 3.06 (s, 1.5H); 3.03 (s, 1.5H); 2.54-2.69 (m, 15 IH); 1.92-2.01 (m, IH); 1.59-1.68 (m, 2H); 1.55 (s, 1.5H); 1.54 (s, 1.5H);

I. 42-1.54 (overlapped m, 4H).

MS (ESI, m/z): 423.98 [M+H⁺] for C19H25N3O6S; t_R = 0.73 min.

Preparation I: (4-(3-hydroxy-3-methylbut-l-yn-l-yl)phenyl)boronic acid:

A mixture of 4-iodophenylboronic acid (2.48 g; 10 mmol; commercial), Pd(PPh3)4 (0.17 g; 20 0.15 mmol) in pyrrolidine (10 mL) was flushed with nitrogen for 15 min. The mixture was cooled to 0°C and 2-methyl-3-butyn-2-ol (1.68 g; 20 mmol; commercial) was added. The reaction was stirred at rt overnight and then concentrated to dryness. The residue was diluted in 2N NaOH (20 mL) and washed twice with DCM (2 x 20 mL). The filtrate was cooled to 0°C and acidified with 2N HC1. The precipitate was collected by filtration, 25 washed with water and purified by CC (DCM-MeOH) to afford the title compound as a white solid (1.4 g; 68% yield).

Ή NMR (i/₆-DMSO) δ: 8.04-8.14 (br. s, 2H); 7.76 (d, J = 8.0 Hz, 2H); 7.34 (d, J = 8.0 Hz, 2H); 5.35-5.51 (br. s, IH); 1.46 (s, 9H).

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Preparation J: 3-(4-iodophenyl)oxetan-3-ol:

A solution of 1,4-diiodobenzene (0.800 g; 2.43 mmol) in THF (8 mL) was treated at -78°C with BuLi (1.683/ in Hex; 2.23 mL). After stirring at this temperature for 30 min, the solution was treated with a suspension of 3-oxetanone (0.24 g; 3.34 mmol, commercial) in

THF (3 mL). The reaction mixture was allowed to reach rt and was further stirred overnight. The reaction mixture was treated with 10% aq. NaHSO4 solution (4 mL) and diluted water (20 mL) and EA (30 mL). The aq. layer was extracted with EA (30 mL). The combined org. layers were washed with brine (50 mL), dried over MgSCL, filtered and concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title 10 compound as a white solid (0.2 g; 55% yield).

Ή NMR (i/₆-DMSO) 5: 7.73 (d, J = 8.5 Hz, 2H); 7.39 (d, J = 8.5 Hz, 2H); 6.39 (s, 1H);

4.73 (d, J = 6.8 Hz, 2H); 4.60 (d, J = 6.8 Hz, 2H).

Preparation K: 3-(iodoethynyl)oxetan-3-ol:

To a solution of 3-ethynyloxetan-3-ol (1.097 g; 11.2 mmol; commercial) in MeOH 15 (50 mL) and aq. KOH (28 mL) was added iodine (3.549 g; 14 mmol). The reaction mixture was stirred for 2 h at rt. Water (150 mL) and DCM (500 mL) were added. The aq. layer was extracted with EA (500 mL). The org. layer was washed with brine, dried over MgSO4, filtered and concentrated down to afford the desired compound as a light yellow solid (2.21 g; 88% yield).

Ή NMR (i/₆-DMSO) 5: 4.60 (d, J = 6.5 Hz, 2H); 4.45 (d, J = 6.5 Hz, 2H).

Preparation L: ((77?,27?)-2-(4-iodophenyl)cyclopropyl)methanol and ((75,25)-2-(4-iodophenyl)cyclopropyl)methanol:

Rac-(irazis-2-(4-iodophenyl)cyclopropyl)methanol (0.956 g; prepared as described in WO 2005/103032) was separated by semi-preparative chiral HPLC Method B 25 (Hept-EtOH 3-1; flow rate: 16 mL/min, UV detection at 210 nM); the respective retention times (flow rate: 0.8 mL/min) were 5.7 and 7.1 min. The title enantiomers were obtained as white solids (0.45 g each).

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First-eluting enantiomer, (7/?,2/?)-configuratcd:

Ή NMR (ί/s-DMSO) δ: 7.56 (d, J = 8.2 Hz, 2H); 6.89 (d, J = 8.2 Hz, 2H); 4.53-4.69 (m, 1H); 3.40-3.51 (m, 1H); 3.31-3.39 (overlapped m, 1H); 1.71-1.81 (m, 1H); 1.18-1.31 (m, 1H); 0.76-0.94 (m, 2H).

[a]_D = -61° (c = 1.04; MeOH).

Second-eluting enantiomer, (7_tS',2_tS)-configurated:

Ή NMR (i/₆-DMSO) δ: 7.56 (d, J = 8.2 Hz, 2H); 6.89 (d, J = 8.2 Hz, 2H); 4.55-4.63 (m, 1H); 3.39-3.51 (m, 1H); 3.27-3.38 (overlapped m, 1H); 1.71-1.80 (m, 1H); 1.18-1.31 (m, 1H); 0.77-0.93 (m, 2H).

[a]_D = +62° (c = 1.04; MeOH).

The respective absolute configurations of these compounds have been determined though transformation of the second-eluting enantiomer into the corresponding (S) and (R) α-methoxy-a-trifluoromethylphenylacetyl esters and the subsequent analysis of their NMR spectra as described by Tsuda et al. in Chem. Pharm. Bull. (2003), 51, 448-451.

Preparation M: (l-(4-ethynylphenyl)cyclopropyl)methanol:

Starting from (l-(4-iodophenyl)cyclopropyl)methanol (0.660 g; 2.4 mmol; commercial) and TMS-acetylene (0.51 mL; 1.5 eq.), and proceeding in analogy to Preparation G, steps G.i and G.ii (yields: Sonogashira coupling: 96%; silyl cleavage: 39% yield), the title compound was obtained, after purification by CC (Hept-EA), as a yellow solid (0.167 g).

Ή NMR (ί/s-DMSO) 5: 7.37 (d, J = 8.2 Hz, 2H); 7.29 (d, J = 8.2 Hz, 2H); 4.68 (t, J = 5.7 Hz, 1H); 4.08 (s, 1H); 3.53 (d, J = 5.6 Hz, 2H); 0.81-0.92 (m, 2H); 0.67-0.79 (m, 2H).

Preparation N: (l-(4-ethynylphenyl)cyclopropyl)methanamine:

In a 7 ml flask, [l-(4-bromophenyl)cyclopropyl]methanamine (0.108 g; 0.479 mmol; 25 commercial), bis(tri-7eri-butylphosphine)palladium (0.021 g; 0.04 mmol), cesium fluoride (0.145 g; 0.96 mmol), degassed dioxane (1.8 mL) and ethynyltri-n-butyltin (0.21 mL; 0.71 mmol) were introduced successively. The solution was stirred at 80°C for 30 min. The mixture was concentrated to dryness and purified by CC (DCM-MeOH) to afford the title compound (still contaminated by unknown impurities) as a brown foam (0.1 g).

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Ή NMR (Λ-DMSO) δ: 7.40 (d, J = 8.4 Hz, 2H); 7.31 (d, J = 8.4 Hz, 2H); 4.13 (s, IH); 2.82 (s, 2H); 0.84-0.90 (m, 2H); 0.74-0.77 (m, 2H).

Preparation O: 2-(4-ethynylphenyl)-2-methylpropan-l-ol:

Starting from 2-(4-bromophenyl)-2-methylpropan-l-ol (0.742 g; 3.2 mmol; commercial) 5 and proceeding in analogy to Preparation N, the title compound was obtained, after purification by CC (Hept-EA), as an ochre solid (0.54 g; 96% yield).

Ή NMR (Λ-DMSO) : 7.33-7.42 (m, 4H); 4.69 (t, J = 5.4 Hz, IH); 4.09 (s, IH); 3.40 (d, J = 5.4 Hz, 2H); 1.20 (s, 6H).

Preparation P: ((15,25)-2-(bromoethynyl)cyclopropyl)methyl acetate AND ((//?, 2/?)-2-(bromoethy ny l)cy clopropy l)methy 1 acetate:

P. i. ((1 S*, 2 S*)-2-(2,2-dibromovinyl)cyclopropyl)methyl acetate:

To a solution of CBr4 (30.0 g; 88.9 mmol) in DCM (60 mL) cooled at -20°C, was added dropwise over 45 min a solution of PPh₃ (45.8 g, 175 mmol) in DCM (100 mL). The mixture was kept stirred at this temperature for 30 min and then cooled to -78°C. A 15 solution of ((7S'*,2S'*)-2-formylcyclopropyl)methyl acetate (6.18 g, 43.5 mmol, prepared as described in WO 2012/154204) in DCM (80 mL) was added dropwise over 45 min, keeping the internal temperature below -70°C. The mixture was stirred at this temperature for 30 min and allowed to warm to rt over 1 h. The solvent was removed in vacuo and the residue was purified by CC (EA-Hept) to afford the title acetate as a clear oil (4.84 g; 20 37% yield).

Ή NMR (CDC1₃) 5: 5.84 (d, J = 9.0 Hz, IH); 3.97 (m, 2H); 2.07 (s, 3H); 1.61 (m, IH);

1.33 (m, IH); 0.78-0.92 (m, 2H).

MS (ESI, m/z) : 295.0 [M+H⁺] for C₈Hio0₂Br2; t_R = 0.87 min.

P. ii. ((IS,2S)-2-(bromoethynyl)cyclopropyl)methyl acetate

AND ((lR,2R)-2-(bromoethynyl)cyclopropyl)methyl acetate:

To a solution of intermediate P.i (3.94 g; 13.2 mmol) in THF (75 mL) was added TBAF trihydrate (23.2 g; 72.8 mmol). The reaction mixture was heated at 60°C for 4 h. The reaction mixture was cooled to rt and diluted with diethyl ether (150 mL). The org. phase was washed with water (60 mL) and brine (60 mL), dried over MgSCU and concentrated to

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-86dryness. The residue was purified by CC (EA-Hept) to afford the title compound as a yellow oil (1.76 g, 61% yield). The racemic product was separated by semi-preparative chiral HPLC Method B (Hept-EtOH 9-1; flow rate: 20 mL/min, UV detection at 223 nm), the respective retention times (flow rate: 0.8 mL/min) were 5.9 and 8.7 min. The title enantiomers were obtained as clear oils (0.64 g each).

First-eluting enantiomer, (/V2M-conf'iguratcd:

Ή NMR (CDCh) δ: 3.97 (dd, J = 6.5, 11.7 Hz, 1H); 3.84 (dd, J = 7.5, 11.7 Hz, 1H); 2.06 (s, 3H); 1.50 (m, 1H); 1.25 (m, 1H); 0.97 (m, 1H); 0.76 (m, 1H).

[a]_D = +96° (c = 1.03; MeOH).

Second-eluting enantiomer, (7R,2R)-configurated:

[a]_D = -94° (c = 1.01; MeOH).

The respective absolute configurations of these compounds have been determined though transformation of the second-eluting enantiomer into the corresponding (5) and (R) a-methoxy-oc-trifluoromethylphenylacetyl esters and the subsequent analysis of their NMR spectra as described by Tsuda et al. in Chem. Pharm. Bull. (2003), 51, 448-451.

Preparation Q: ((l-(bromoethynyl)cyclopropyl)methoxy)(toT-butyl)diphenylsilane:

To a mixture of (dibromomethyl)triphenylphosphonium bromide (8.527 g; 16.6 mmol) and THF (40 mL) was added a solution of tBuOK (\M in THF; 16.6 mL; 16.6 mmol). The resulting dark brown solution was stirred for 3 min at rt, then cooled to 0°C. A solution of l-(((ieri-butyldiphenylsilyl)oxy)methyl)cyclopropanecarbaldehyde (2.2 g; 6.62 mmol; prepared as described in WO 2010/135536) in THF (23 mL) was added drop wise. The reaction was stirred at 0°C for 40 min. The reaction mixture was cooled to -78°C and tBuOK (1ΛΤ in THF; 29.1 mL; 29.1 mmol) was added rapidly and stirred at -78°C for 30 min. The reaction mixture was quenched with brine (150 mL). The aq. layer was separated and extracted with diethyl ether (3 x 150 mL). The combined org. phases were washed with brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a colourless oil (2.052 g; 75 % yield).

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Ή NMR (rtd-DMSO) δ: 7.59-7.70 (m, 4H); 7.37-7.53 (m, 6H); 3.56 (s, 2H); 1.01 (s, 9H); 0.82-0.89 (m, 2H); 0.71-0.76 (m, 2H).

Preparation R: (l-(3-fluoro-4-iodophenyl)cyclopropyl)methanol:

R.i. Methyl l-(4-bromo-3-fluorophenyl)cyclopropanecarboxylate:

To an ice-chilled mixture of l-(4-bromo-3-fluorophenyl)cyclopropanecarboxylic acid (1.188 g; 4.59 mmol; commercial) in MeOH (9 mL), was added dropwise thionyl chloride (0.7 mL; 9.6 mmol). The mixture was stirred at 0°C for 1 h and then at rt for 17 h. The mixture was concentrated to dryness and the residue was partitioned between sat. aq. NaHCO3 (30 mL) and EA (30 mL). The two layers were separated. The aq. phase was 10 extracted with EA (30 mL). The combined org. layers were washed with brine (45 mL), dried over MgSO4, filtered and concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a yellow oil (0.501 g; 40% yield).

Ή NMR (rL-DMSO) 5: 7.63 (t, J = 8.3 Hz, IH); 7.39 (dd, J= 1.9, 10.1 Hz, IH); 7.15 (dd, J = 1.9, 8.3 Hz, IH); 3.56 (s, 3H); 1.46-1.51 (m, 2H); 1.22-1.28 (m, 2H).

R.ii. (l-(4-bromo-3-fluorophenyl)cyclopropyl)methanol:

To a solution of intermediate R.i (0.491 g; 1.792 mmol) in DCM (9 mL) cooled to -78°C was added dropwise DIBAH (1Λ7 in DCM; 5.6 mL; 5.6 mmol). The solution was stirred at -78°C for 20 min. The reaction was allowed to warm to 0°C. Water (0.224 mL), 15% NaOH (0.224 mL), water (0.56 mL) were added carefully. The mixture was stirred for 20 15 min at this temperature and MgSCU was added. The mixture was filtered and washed with DCM and EA. The filtrate was concentrated to dryness to give the title compound as a yellow oil (0.424 g; 97% yield).

Ή NMR (rL-DMSO) 5: 7.57 (t, J = 8.0 Hz, IH); 7.26 (dd, J = 1.9, 10.7 Hz, IH); 7.08 (dd, J = 1.9, 8.0 Hz, IH); 4.77 (t, J = 5.8 Hz, IH); 3.51 (d, J = 5.5 Hz, 2H); 0.82-0.89 (m, 2H); 25 0.76-0.82 (m, 2H).

R. Hi. (I-(3-fluoro-4-iodophenyl)cyclopropyl)methanol:

To a solution of intermediate R.ii (0.405 g; 1.65 mmol) in 1,4-dioxane (2.2 mL) in a vial was added Nal (0.496 g; 3.31 mmol) and then Cui (0.063 g; 0.331 mmol). The reaction mixure was degassed and trans-7V,N'-dimethylcyclohexane-l,2-diamine (0.104 mL,

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- 88 0.661 mmol) was added. The mixture was degassed and stirred at 125°C for 17 h. The suspension was cooled down to rt. The residue was filtered and washed with EA (10 mL). The filtrate was washed with water (10 mL). The aq. layer was extracted with EA (2xl0mL). The combined org. layers were washed with brine (20 mL), dried over MgSCL and filtered before being concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title product as a yellow oil (0.352 g; 73% yield).

Ή NMR (t/6-DMSO) δ: 7.70 (dd, J = 7.0, 8.1Hz, IH); 7.16 (dd, J = 2.0, 10.0 Hz, IH); 6.93 (dd, J = 2.0, 8.1Hz, IH); 4.75 (t, J = 5.7 Hz, IH); 3.51 (d, J = 5.7 Hz, 2H); 0.84-0.87 (m, 2H); 0.76-0.79 (m, 2H).

Preparation S: l-(2-hydroxyethyl)-3-(4-iodophenyl)imidazolidin-2-one:

S. i. l-(4-bromophenyl)-3-(2-hydroxyethyl)imidazolidin-2-one AND l-(2-hydroxyethyl)-

3-(4-iodophenyl)imidazolidin-2-one:

Cui (0.0762 g; 0.4 mmol), (lR,2R)-l,2-diaminocyclohexane (0.137 g; 1.2 mmol) and K2CO3 (1.11 g; 8 mmol) were added to degassed 1,4-dioxane (15 mL). The reaction mixture was degassed and l-(2-hydroxyethyl)-imidazolidinone (0.521 g; 4 mmol) and

1- bromo-4-iodobenzene (1.132 g; 4 mmol) were added. The resulting mixture was heated to reflux at 110°C for 15 h. The reaction mixture was cooled to rt, filtered through a Celite and the Celite bed was washed with chloroform. The filtrate was dried over Na2SC>4 and filtered before being concentrated to dryness. The residue was purified by CC (Hept-EA) to afford a 4-1 unseparable mixture of l-(4-bromophenyl)-3-(2-hydroxyethyl)imidazolidin-

2- one and l-(2-hydroxyethyl)-3-(4-iodophenyl)imidazolidin-2-one as a white solid (0.445 g; 39% yield).

MS (ESI, m/z): 285.04 [M+H⁺] for ^ιΗι₃Ν₂Ο₂Βγ; t_R = 0.69 min.

MS (ESI, m/z): 332.93 [M+H⁺] for C11H13N2O2I; t_R = 0.71 min.

S.ii. l-(2-hydroxyethyl)-3-(4-iodophenyl)imidazolidin-2-one:

Starting from intermediate S.i (0.06 g; 0.119 mmol) and proceeding in analogy to Preparation R, step R.iii, the title compound was obtained as a yellow solid (0.345 g; 53% yield).

Ή NMR (CDCh) δ: 7.61 (d, J = 8.9 Hz, 2H); 7.32 (d, J = 8.9 Hz, 2H); 3.77-3.86 (m, 4H);

3.56-3.64 (m, 2H); 3.41-3.48 (m, 2H); 2.64-2.77 (m, IH).

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MS (ESI, m/z): 332.93 [M+H⁺] for C11H13N2O2I; t_R = 0.71 min.

Preparation T: 2V-(2-fluoro-4-iodophenyl)-2-hydroxyacetamide:

To a solution of 2-((4-bromo-2-fluorophenyl)amino)-2-oxoethyl acetate (1.0 g; 3.45 mmol; commercial) in 1,4-dioxane (2.3 mL) were added /rans-7V,N'-dimethylcyclohexane-l,25 diamine (0.06 mL; 0.38 mmol), Nal (1.03 g; 6.9 mmol) and Cui (0.066 g; 0.35 mmol). The reaction mixture was irradiated in a micro wave oven at 170°C for 30 min and then at 180°C for 30 min. Water (20 mL) and EA (50 mL) were added. The aq. layer was extracted with EA (45 mL). The combined org. layers were washed with brine, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in MeOH (20 mL) and K2CO3 (2.5 g; 17.2 mmol) was added. The reaction was stirred at rt for 10 min. EA (100 mL) and water (60 mL) were added. The aq. phase was extracted with EA (100 mL).

The combined org. phases were washed with brine, dried over MgSO4 and filtered. After concentration to dryness of the filtrate, the title compound was obtained as a brown solid (0.8 g; 79% yield).

Ή NMR (i/₆-DMSO) δ: 7.66-7.78 (m, 2H); 7.51-7.57 (m, 1H); 5.85 (t, J = 5.9 Hz, 1H); 4.02 (d, J = 5.9 Hz, 2H).

Preparation U: (l-(5-iodopyridin-2-yl)cyclopropyl)methanol:

Starting from (l-(5-bromopyridin-2-yl)cyclopropyl)methanol (0.98 g; 4.28 mmol; commercial) and proceeding in analogy to Preparation R, step R. iii, the title compound was 20 obtained, after purification by CC (Hept-EA), as a white solid (0.97 g; 82% yield).

Ή NMR (flfc-DMSO) δ: 8.63 (d, J = 2.0 Hz, 1H); 8.03 (dd, J = 2.0, 8.4 Hz, 1H); 7.37 (d, J = 8.4 Hz, 1H); 4.78 (t, J = 5.5 Hz, 1H); 3.70 (d, J = 5.5 Hz, 2H); 1.04-1.10 (m, 2H); 0.87-0.93 (m, 2H).

MS (ESI, m/z): 275.77 [M+H⁺] for C9H10NOI; t_R = 0.55 min.

Preparation V: (l-(6-iodopyridin-3-yl)cyclopropyl)methanol:

Starting from (l-(6-bromopyridin-3-yl)cyclopropyl)methanol (0.42 g; 2.29 mmol; commercial) and proceeding in analogy to Preparation R, step R. iii, the title compound was obtained, after purification by CC (Hept-EA), as a colourless oil (0.35 g; 55% yield).

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Ή NMR (Λ-DMSO) δ: 8.30 (dd, J = 0.6, 2.6 Hz, 1H); 7.72 (dd, J = 0.6, 8.1Hz, 1H); 7.40 (dd, J = 2.6, 8.1Hz, 1H); 4.80 (t, J = 5.7 Hz, 1H); 3.48 (d, J = 5.7 Hz, 2H); 0.83-0.87 (m, 2H); 0.77-0.80 (m, 2H).

MS (ESI, m/z): 275.78 [M+H⁺] for C9H10NOI; t_R = 0.63 min.

Preparation W: 4-((l-(4-iodophenyl)cyclopropyl)methyl)morpholine:

W.i. 4-((l-(4-bromophenyl)cyclopropyl)methyl)morpholine:

To a solution of l-(4-bromophenyl)cyclopropanecarbaldehyde (0.405 g; 1.8 mmol, commercial) in MeOH (5.8 mL) was added 3A molecular sieves (0.05 g) and morpholine (0.174 mL; 1.98 mmol). The reaction was stirred at rt overnight under nitrogen.

Morpholine (0.2 mL; 2.27 mmol) was added and the mixture was stirred at 70°C for 20 h. The reaction mixture was cooled to 0°C and DCE (5.8 mL) was added followed by sodium triacetoxyborohydride (1.144 g; 5.4 mmol). The reaction mixture was stirred at this temperature for 10 min, then at rt for 30 min. Sat. aq. NaHCCh (20 mL) and DCM (25 mL) were added. The mixture was filtered and the phases were separated. The aq. layer was extracted with DCM-MeOH (9-1, 3x20 mL). The combined org. layers were dried over

MgSCU, filtered and concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a colourless oil (0.413 g; 78% yield).

Ή NMR (Λ-DMSO) δ: 7.42 (d, J = 8.5 Hz, 2H); 7.27 (d, J = 8.5 Hz, 2H); 3.43-3.47 (m, 4H); 2.48 (s, 2H); 2.32-2.40 (m, 4H); 0.79-0.82 (m, 2H); 0.70-0.74 (m, 2H).

MS (ESI, m/z): 295.92 [M+H⁺] for CuHisNOBr; t_R = 0.58 min.

W.ii. 4-((l-(4-iodophenyl)cyclopropyl)methyl)morpholine:

Starting from intermediate W.i (0.41 g; 1.39 mmol) and proceeding in analogy to Preparation R, stepR.iii, the title compound was obtained, after purification by CC (Hept-EA), as a yellow oil (0.29 g; 61% yield).

Ή NMR (Λ-DMSO) δ: 7.59 (d, J = 8.3 Hz, 2H); 7.13 (d, J = 8.3 Hz, 2H); 3.46 (t, J = 4.5 Hz, 4H); 2.48 (s, 2H); 2.30-2.40 (m, 4H); 0.78-0.82 (m, 2H); 0.68-0.74 (m, 2H). MS (ESI, m/z): 343.87 [M+H⁺] for Ci₄HisNOI; t_R = 0.55 min.

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Preparation X: (E)-toT-butyldimethyl((4-(2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-

2-yl)vinyl)benzyl)oxy)silane:

To a solution of ierAbutyl((4-ethynylbenzyl)oxy)dimethylsilane (6.836 g; 27.7 mmol; prepared as described in Allen et al., J. Am. Chem. Soc. (2009), 131(35), 12560-12561) 5 was dissolved in DCM (130 mL) and 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (12 mL;

82.7 mmol) was added. The solution was degassed and tris(triphenylphosphine)rhodium(I) chloride (0.292 g; 0.281 mmol) was added. The mixture was stirred at rt overnight under argon. Tris(triphenylphosphine)rhodium(I) chloride (0.302 g; 0.291 mmol) and 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (6 mL; 41.4 mmol) were added to the mixture 10 which was degassed and stirred at rt for 1 h under argon. The reaction was carefully quenched with sat. NH4CI (150 mL). The phases were separated and the aq. phase was extracted with EA (2 x 150 mL). The combined org. layers were dried over MgSCU and filtered. After concentration of the filtrate to dryness, the residue was purified by CC (Hept-EA) to afford the title compound as an orange oil (5.7 g; 55% yield).

Ή NMR (i/₆-DMSO) 5: 7.55 (d, J = 8.2 Hz, 2H); 7.30 (d, J = 8.2 Hz, 2H); 6.11 (d, J = 18.5 Hz, IH); 4.63-4.73 (m, 3H); 1.24 (s, 12H), 0.90 (s, 9H), 0.07 (s, 6H).

Preparation Y: ((3-(bromoethynyl)bicyclo[l.l.l]pentan- l-yl)methoxy)(ti'/7-butyl)diphenylsilane:

Y. i. Bicyclo[1.1.1]pentane-l, 3-diyldimethanol:

To a solution of dimethyl bicyclo[l.l.l]pentane-l,3-dicarboxylate (1.74 g; 9.45 mmol; commercial) in THF (12 mL), cooled at 0°C was added dropwise L1AIH4 (2.44/in THF;

5.29 mL; 12.7 mmol) over 45 min, keeping IT below 15°C. The suspension was stirred at rt for 3 h. The crude mixture was cooled to 0°C and carefully quenched by water (0.48 mL), 15% aq. NaOH (0.48 mL) and water (1.44 mL). The mixture was stirred at rt 25 for 35 min then THF (17 mL) and MgSO4 were added. The mixture was stirred at rt for min. The mixture was filtered and concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a colourless oil (1.2 g; 99% yield).

Ή NMR (i/₆-DMSO) δ: 4.40 (t, J = 5.5 Hz, 2H); 3.35 (d, J = 5.6 Hz, 4H); 1.46 (s, 6H).

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Y. ii. (3-(((tert-butyldiphenylsilyl)oxy)methyl)bicyclo[1.1.1]pentan-l-yl)methanol:

To a suspension of NaH (60% in mineral oil; 0.23 g; 5.67 mmol) in THF (4.5 mL) was added slowly at rt a solution of intermediate Y.i (0.66 g; 5.16 mmol) in THF (3.3 mL), keeping IT below 27°C. After 1 h stirring, a solution of TBDPS-C1 (1.36 mL; 5.16 mmol) 5 in THF (2.8 mL) was added drop wise over 15 min. The solution was stirred for 4 h, then diluted in Et20 (20 mL). The org. phase was washed with brine (2 x 20 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a colourless oil (0.49 g; 26% yield).

Ή NMR (ok-DMSO) δ: 7.56-7.64 (m, 4H); 7.39-7.50 (m, 6H); 4.43 (t, J = 5.6 Hz, IH); 10 3.64 (s, 2H); 3.36 (d, J = 5.5 Hz, 2H); 1.49 (s, 6H); 1.01 (s, 9H).

Y.iii. 3-(((tert-butyldiphenylsilyl)oxy)methyl)bicyclo[l. 1.1]pentane-l-carbaldehyde:

To a solution of intermediate Y.ii (1.09 g; 2.98 mmol) in DCM (6.9 mL) cooled to -10°C, was added DIPEA (1.59 mL; 9.31 mmol) over 15 min. A solution of Pyr.SCh complex (45%; 1.44 g; 4.07 mmol) in DMSO (4.03 mL) was then dropwise added over 10 min. The 15 reaction mixture was stirred for 1.5 h at 0°C and 1 h at rt. The reaction mixture was partitioned between water (35 mL) and DCM (20 mL). The aq. layer was extracted with DCM (15 mL). The combined org. layers were dried over Na2SC>4, filtered and concentrated to dryness. The residue was co-evaporated with toluene (2x10 mL) and then purified by CC (Hept-EA) to afford the title compound as a colourless oil (0.94 g; 87% 20 yield).

Ή NMR (Λ-DMSO) δ: 9.53 (s, IH); 7.57-7.62 (m, 4H); 7.41-7.49 (m, 6H); 3.68 (s, 2H);

1.86 (s, 6H); 1.01 (s, 9H).

Y.iv. Tert-butyl((3-(2,2-dibromovinyl)bicyclo[1.1.1]'pentan-l-yl)methoxy)diphenylsilane:

To a solution of carbon tetrabromide (1.76 g; 5.25 mmol) in DCM (3.8 mL) cooled 25 at -20°C, was added dropwise over 20 min a solution of triphenylphosphine (2.81 g;

10.3 mmol) in DCM (6.2 mL). The yellow suspension was allowed to warm slowly (over 8 min) to -5°C and was then cooled to -78°C. A solution of intermediate Y.iii (0.94 g;

2.58 mmol) in DCM (4.9 mL) was added dropwise over 50 min at -78°C. The mixture was stirred at this temperature for 30 min. The mixture was allowed to slowly warm to rt (over 30 1 h). The mixture was diluted in Et2O (60 mL), filtered and washed with Et2O. The filtrate was concentrated to dryness and slurried in Et2O (50 mL). The mixture was vigorously

- 93 2015226250 05 Nov 2018 stirred at rt for 30 min. The mixture was filtered, washed with Et20 and the filtrate concentrated to dryness. The residue was then purified by CC (Hept-EA) to afford the title compound as a yellow oil (1.2 g; 89% yield).

Ή NMR (i/₆-DMSO) δ: 7.57-7.61 (m, 4H); 7.41-7.49 (m, 6H); 6.74 (s, IH); 3.64 (s, 2H); 5 1.90 (s, 6H); 1.01 (s, 9H).

Y. v. ((3-(bromoethynyl)bicyclo[1.1.1]'pentan-l-yl)methoxy)(tert-butyl)diphenylsilane:

A solution of intermediate Y.iv (0.45 g; 0.86 mmol) in THF (2 mL) cooled at -78°C was treated with a solution of tBuOK (IM, 3.8 mL). The reaction mixture was stirred for 30 min at -78°C then was diluted with brine (8 mL) and was allowed to reach rt. Et2O 10 (15 mL) was added. The two layers were separated and the aq. phase was extracted with

Et2O (15 mL). The combined org. layers were washed with brine (10 mL), dried over

Na2SO4, filtered and concentrated to dryness to afford the title compound as a yellow oil (0.37 g; 97% yield).

Ή NMR (i/₆-DMSO) δ: 7.55-7.60 (m, 4H); 7.41-7.49 (m, 6H); 3.60 (s, 2H); 1.91 (s, 6H); 15 1.00 (s,9H).

Preparation Z: 4-iodo-2-methylbut-3-yn-2-amine:

Starting from 2-methylbut-3-yn-2-amine (0.5 g; 6 mmol; commercial) and proceeding in analogy to Preparation K, the title compound was obtained as a yellow solid (0.98 g; 78% yield).

Ή NMR (ί/d-DMSO) δ: 2.01 (s, 2H); 1.24 (s, 6H).

MS (ESI, m/z): 210.01 [M+H⁺] for CsHsNI; t_R = 0.33 min.

Preparation AA: 4-iodobenzyl carbamate:

AA.i. 4-iodobenzyl (2,2,2-trichloroacetyl)carbamate:

To a solution of iodobenzylalcool (1 g; 4.27 mmol) in DCM (20 mL) was added at 0°C 25 trichloroacetylisocyanate (0.56 mL; 4.7 mmol; commercial). The mixture was stirred at

0°C for 1 h, allowed to reach rt and stirred at rt for 3 h. Water (20 mL) was added. The aq. layer was extracted with DCM (20 mL). The combined org. phases were dried over MgSCL and filtered. The filtrate was concentrated to dryness to afford the title compound as a beige solid (1.85 g; quant.).

-942015226250 05 Nov 2018

Ή NMR (ίΑ-DMSO) δ: 12.02 (s, 1H); 7.76-7.82 (m, 2H); 7.24-7.31 (m, 2H); 5.21 (s, 2H).

AA.ii. 4-iodobenzyl carbamate:

Intermediate AA.i (1.85 g; 4.38 mmol) was dissolved in MeOH (8 mL). K2CO3 (1.816 g;

13.1 mmol) was added and the mixture was stirred at rt for 4 h. EA (100 mL) was added.

The aq. phase was extracted with EA (100 mL). The combined org. layers were washed with brine, dried over MgSO4, filtered and the filtrate concentrated to dryness. The residue was taken in Et20 (5 mL). The mixture was stirred for 20 min and filtered to afford the title compound as a white solid (1.05 g; 87% yield).

Ή NMR (<A-DMSO) δ: 7.70-7.78 (m, 1H); 7.13-7.20 (m, 1H); 6.39-6.87 (m, 1H); 4.93 (s, 10 1H).

Preparation AB: (3aR,55,6a5)-5-(bromoethynyl)-2,2-dimethyltetrahydro4//-cy clopent a [d] [1,3] dioxole:

Starting from (3aR, 5S,6aS)-5-(2,2-dibromovinyl)-2,2-dimethyltetrahydro4Z/-cyclopenta[i/][l,3]dioxole (2.06 g; 6.32 mmol; prepared as described in 15 WO 2013/170030) and proceeding in analogy to Preparation N, stepN.v, the title compound was obtained as a yellow oil (1.37 g; 88% yield).

Ή NMR (CDCI3) δ: 4.60-4.63 (m, 2H); 2.85-2.93 (m, 1H); 2.12-2.17 (m, 2H); 1.51-1.60 (overlapped m, 2H); 1.41 (s, 3H); 1.26 (s, 3H).

Preparation AC: (l-(4-iodophenyl)cyclopropyl)methyl carbamate:

Starting from (l-(4-iodophenyl)cyclopropyl)methanol (0.887 g, 3.24 mmol), and proceeding as described in Preparation AA, steps AA.i and AA.ii, the title carbamate was obtained as a white solid (0.63 g; 59% yield over the two steps).

Ή NMR (<A-DMSO) δ: 7.63 (m, 2H); 7.08-7.13 (m, 2H); 6.31-6.64 (m, 2H); 4.05 (s, 2H); 0.92-0.98 (m, 2H); 0.83-0.89 (m, 2H).

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Preparation AD: l-(bromoethynyl)cyclopropyl)methyl carbamate:

AD. i. (I-(bromoethynyl)cyclopropyl)methanol:

To a solution of the compound of Preparation Q (0.5 g; 1.21 mmol) in THF (2 mL) was added TBAF (lA/in THF; 2.42 mL; 2.42 mmol). The mixture was stirred at rt for 1 h. Sat.

aq. NH4CI (5 mL) was added and the mixture was extracted with EA (2x5 mL). The org. layer was washed with brine, dried over MgSO₄ and filtered. The filtrate was concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a colourless oil (0.175 g; 83% yield).

Ή NMR (i/₆-DMSO) 5: 4.90 (t, J = 6.0 Hz, 1H); 3.32 (d, J = 6.0 Hz, 2H); 0.76-0.80 (m, 10 2H); 0.72-0.76 (m, 2H).

AD. ii. (I-(bromoethynyl)cyclopropyl)methyl carbamate:

Starting from intermediate AD.i (0.175 g; 1 mmol) and proceeding successively in analogy to Preparation AA, steps AA.i (94% yield) and AA.ii (64% yield), the title compound was obtained, after purification by CC (Hept-EA), as a white solid (0.13 g).

Ή NMR (i/₆-DMSO) 5: 6.11-7.10 (m, 2H); 3.82 (s, 2H); 0.85-0.89 (m, 2H).

Preparation AE: (((77?,27?)-2-(bromoethynyl)-

2-methylcyclopropyl)methoxy)(ter/-butyl)diphenylsilane:

AE. i. ((lR,2R)-2-(hydroxymethyl)-l-methylcyclopropyl)methyl acetate:

To a solution of ((77?,27?)-2-formyl-l-methylcyclopropyl)methyl acetate (0.925 g; 20 5.92 mmol; prepared as described in WO 2012/154204) in MeOH (10 mL) was added

NaBH4 (0.297 g; 7.7 mmol) portion-wise at 0°C. The reaction was stirred for 80 min at 0°C then for 30 min at rt. Water (10 mL) and DCM (40 mL) were added and the phases were separated. The aq. layer was extracted with DCM-MeOH 9-1 (2x15 mL) and the combined org. layers were dried over Na₂SO4 and filtered. The filtrate was evaporated 25 under reduced pressure to give the title compound as a colourless oil (0.968 g; quant.).

Ή NMR (CDCh) δ: 3.89 (d, J = 11.3 Hz, 1H); 3.82 (d, J = 11.3 Hz, 1H); 3.74-3.80 (m,

1H); 3.49-3.56 (m, 1H); 2.08 (s, 3H); 1.19 (s, 3H); 1.09-1.15 (m, 1H); 0.70-0.76 (m, 1H); 0.27-0.31 (m, 1H).

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AE. ii. ((lR,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-l-methylcyclopropyl)methyl acetate:

To a solution of intermediate AE.i (0.94 g; 5.92 mmol) in DCM (12 mL) was added imidazole (0.819 g; 11.9 mmol). The solution was cooled to 0°C and TBDPSC1 (1.6 mL;

6.03 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 20 min then at rt for 2.5 h. Aq. NaHSCU (15%, 20 mL) was added. The aq. phase was extracted with DCM (10 mL). The combined org. layers were dried over MgSCU, filtered and the filtrate concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a colourless oil (2.29 g; 97% yield).

Ή NMR (CDCh) δ: 7.66-7.70 (m, 4H); 7.35-7.45 (m, 6H); 3.84 (s, 2H); 3.82-3.88 (overlapped m, 1H); 3.46-3.55 (m, 1H); 2.07 (s, 3H); 1.14 (s, 3H); 1.05 (s, 9H), 1.03-1.11 (overlapped m, 1H); 0.59-0.65 (m, 1H); 0.14-0.19 (m, 1H).

MS (ESI, m/z): 397.01 [M+H⁺] for C₂4H32O₃Si; t_R = 1.13 min.

AE.iii. ((lR,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-l-methylcyclopropyl)methanol:

To a solution of intermediate AE.ii (2.29 g; 5.77 mmol) in MeOH (50 mL) was added K2CO3 (1.59 g; 11.5 mmol). The suspension was stirred at rt for 4 h. The reaction mixture was filtered and the solid was washed with DCM. The filtrate was evaporated under reduced pressure. The residue was partitioned between water (30 mL) and DCM (40 mL). The aq. layer was extracted with DCM-MeOH 9-1 (40 mL) and EA-MeOH 9-1 (40 mL).

The combined org. layers were dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by CC (Hept-EA) to afford the title compound as a colourless oil (1.59 g; 78% yield).

'HNMR (CDCI3) δ: 7.66-7.72 (m, 4H); 7.36-7.45 (m, 6H); 3.86 (dd, J = 5.8, 11.1 Hz, 1H);

3.49 (dd, J = 8.7, 11.1 Hz, 1H); 3.38 (d, J =11.0 Hz, 1H); 3.30 (d, J =11.0 Hz, 1H);

1.16 (s,3H); 1.05 (s, 9H); 0.95-1.02 (m, 1H); 0.55 (dd, J = 4.8, 9.0 Hz, 1H); 0.12-0.16 (m,

1H).

AE. iv. (((1R, 2R)-2-(bromoethynyl)-2-methylcyclopropyl)methoxy) (tertbutyl) diphenylsilane:

Starting from intermediate AE.iii (1.59 g; 4.5 mmol) and proceeding successively in 30 analogy to Preparation Y, step Y.iii (92% yield), Preparation P, step P.i (85% yield) and

-972015226250 05 Nov 2018

Preparation Y, step Y.v (98% yield), the title compound was obtained as a yellow oil (1-48 g).

Ή NMR (CDCh) δ: 7.65-7.72 (m, 4H); 7.36-7.46 (m, 6H); 3.79 (dd, J = 5.6, 11.5 Hz, 1H);

3.49 (dd, J = 8.4, 11.5 Hz, 1H); 1.43-1.51 (m, 1H); 1.25 (s, 3H); 1.05 (s, 9H); 1.02 (dd, 5 J = 4.7, 9.1 Hz, 1H); 0.37 (dd, J = 4.7, 6.4 Hz, 1H).

Preparation AF: (l-(4-ethynylphenyl)cyclopropyl)methyl dimethylglycinate:

To a solution of the compound of Preparation M (0.20 g; 1.18 mmol) in DCM (13 mL) were added Α',Α'-diiucthylglycinc (0.13 g; 1.18 mmol), EDC.HC1 (0.31 g; 1.6 mmol) and DMAP (0.19 g; 1.53 mmol). The reaction was stirred at rt for 27 h. 5% aq. NaHCCh 10 (5 mL) was added to the reaction mixture and. the aq. layer was extracted with DCM (2 x 20 mL). The combined org. layers were dried over MgSO₄, filtered and concentrated to dryness. The residue was purified by CC (DCM-MeOH) to afford the title compound as a yellow oil (0.23 g, 76% yield).

Ή NMR (%-DMSO) 5: 7.37-7.41 (m, 2H); 7.26-7.30 (m, 2H); 4.21 (s, 2H); 4.13 (s, 1H); 15 3.10 (s, 2H); 2.17 (s, 6H); 0.97-1.01 (m, 2H); 0.90-0.94 (m, 2H).

MS (ESI, m/z): 258.07 [M+H⁺] for CieHigNCh; t_R = 0.63 min.

Preparation AG: l-(iodoethynyl)cyclopropan-l-amine hydrochloride:

AG.i. Tert-butyl (l-(iodoethynyl)cyclopropyl)carbamate:

Starting from Ze/7-butyl 1-ethynylcyclopropylcarbamate (0.855 g; 4.88 mmol; commercial) 20 and proceeding in analogy to Preparation K (91% yield), the title compound was obtained as a yellow solid (1.36 g).

Ή NMR (CDCh) δ: 4.85-5.16 (br. s, 1H); 1.49 (s, 9H); 1.18-1.24 (m, 2H); 1.05-1.11 (m, 2H).

AG.ii. l-(iodoethynyl)cyclopropan-l-amine hydrochloride:

A solution of intermediate AG.i (0.6 g; 1.95 mmol) in HCI (47V in dioxane; 4 mL;

mmol) was stirred at rt for 2 h. The mixture was concentrated to the dryness and the residue was triturated in Et₂O, filtered, and washed with Et₂O to afford the title compound as a beige solid (0.354 g, 75% yield).

Ή NMR (%-DMSO) 5: 8.74-8.81 (br. s, 3H); 1.24-1.29 (m, 2H); 1.16-1.20 (m, 2H).

- 98 2015226250 05 Nov 2018

Preparation AH: tert-butyl (3-(iodoethynyl)oxetan-3-yl)carbamate:

AH. i. Tert-butyl (3-((trimethylsilyl)ethynyl)oxetan-3-yl)carbamate:

To a solution of 3-((trimethylsilyl)ethynyl)oxetan-3-amine hydrochloride (1.39 g;

6.75 mmol; commercial) in DCM (34 mL) were added TEA (2.2 mL; 15.8 mmol) and 5 BOC2O (3.09 g; 14.2 mmol). The reaction mixture was stirred at rt overnight. BOC2O (1.3 g;

6.31 mmol) was added again and the reaction was stirred for 6 h. The reaction mixture was diluted with DCM (5 mL) and sat. aq. NaHCCh (5 mL) was added. The phases were separated and the aq. layer was extracted twice with DCM (2x5 mL). The combined org. layers were washed with brine (5 mL), dried over MgSCL, filtered and the filtrate 10 concentrated to dryness to afford the title compound, slightly contaminated by BOC2O, as a yellow oil (3.34 g).

^NMRiCDCh) δ: 4.72-4.81 (m, 4H); 3.05 (br. s, 1H); 1.47 (s, 9H); 0.18 (s, 9H).

AH.ii. Tert-butyl (3-(iodoethynyl)oxetan-3-yl)carbamate:

Starting from intermediate AH.i (crude; 1.8 g; 6.75 mmol) and proceeding successively in 15 analogy to Preparation G, step G.ii (quant, yield) and Preparation K (92% yield), the title compound was obtained as a beige solid (1.61 g).

Ή NMR (CDCh) δ: 4.94-5.10 (br. s, 1H); 4.81-4.85 (m, 2H); 4.70-4.75 (m, 2H); 1.47 (s, 9H).

Preparation Al: (l-(4-iodophenyl)cyclobutyl)methanol:

Starting from (l-(4-bromophenyl)cyclobutyl)methanol (0.64 g; 2.66 mmol, commercial) and proceeding in analogy to Preparation R, step R.iii (93% yield), the title compound was obtained, after purification by CC (Hept-EA), as a colourless oil (0.71 g).

Ή NMR (CDCh) δ: 7.64-7.67 (m, 2H); 6.89-6.92 (m, 2H); 3.73 (d, J = 5.3 Hz, 2H);

2.26-2.32 (m, 2H); 2.19-2.27 (m, 2H); 2.03-2.13 (m, 1H); 1.84-1.93 (m, 1H).

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Preparation AJ: 2-(3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-

2-yl)phenoxy)ethan-l-ol:

AJ. i. Ethyl 2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetate:

A mixture of bis(pinacolato)diboron (0.97 g; 3.8 mmol), Pd(dppf)C12 (0.21 g; 0.26 mmol) and KOAc (1.07 g; 10.9 mmol) was flushed with nitrogen for 15 min and treated with a solution of 2-(4-bromo-3-fluorophenoxy)acetate (1 g; 3.61 mmol; commercial) in dioxane (14.5 mL). The reaction mixture was heated to reflux overnight. After cooling, the reaction mixture was filtered and the filtrate concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the desired compound as a yellow oil (0.82 g; 70% yield).

Ή NMR (ίΑ-DMSO) 5: 7.53-7.57 (m, 1H); 6.75-6.81 (m, 2H); 4.86 (s, 2H); 4.17 (q, J = 7.1 Hz, 2H); 1.28 (s, 12H); 1.21 (t, J = 7.1 Hz, 3H).

MS (ESI, m/z): 324.9 [M+H⁺] for C16H22NO5BF; t_R = 0.93 min.

AJ.ii. 2-(3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)ethan-l-ol:

NaBH4 (0.14 g; 3.76 mmol) was added portion-wise to an ice chilled ethanol (4.5 mL) 15 solution of intermediate AJ.i (0.81 g; 2.5 mmol). The mixture was stirred for 2 h in the ice bath melting. Acetone (0.37 mL), EA (5 mL) and water (10 mL) were added sequentially at rt. Solvents were distilled off under reduced pressure. EA (20 mL) was added to the resulting residue. The org. phase was washed with water (10 mL) and brine (10 mL), dried over Na₂SO4, filtered. The filtrate was concentrated to dryness and the residue was purified 20 by CC (DCM-MeOH) to afford the title compound as a colourless oil (0.48 g; 68% yield).

Ή NMR (ί/s-DMSO) 5: 7.52-7.57 (m, 1H); 6.79 (dd, J = 2.3, 8.4 Hz, 1H); 6.74 (dd, J = 2.2, 11.5 Hz, 1H); 4.90 (t, J = 5.5 Hz, 1H); 4.00-4.05 (m, 2H); 3.68-3.73 (m, 2H); 1.28 (s, 12H).

Preparation AK: ((!/?,25,3s)-3-(iodoethynyl)cyclopropane-l ,2-diyl)dimethanol:

Starting from ((7R,25,3x)-3-ethynylcyclopropane-l,2-diyl)dimethanol (0.168 g; 0.85 mmol; prepared as described in WO 2013/170030) and proceeding in analogy to Preparation K (28% yield), the title compound was obtained, after purification by CC (Hept-EA), as a yellow oil (0.06 g).

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Ή NMR (ί/s-DMSO) δ: 4.60 (t, J = 5.6 Hz, IH); 4.55 (t, J = 5.3 Hz, IH); 3.40-3.45 (m, 3H); 3.14-3.20(m, IH); 1.47 (dd, J = 4.8, 8.2 Hz, IH); 1.07-1.13 (m, IH); 0.98-1.03 (m, IH).

Preparation AL: (4-ethynyl-3-fluorophenyl)methanol:

Starting from (3-fluoro-4-iodophenyl)methanol (0.510 g; 2.0 mmol; commercial) and proceeding in analogy to Procedure C (96% yield) and Preparation G, step G.ii (79% yield), the title compound was obtained as a colourless oil (0.23 g).

Ή NMR 5 (<7_d-DMSO) δ: 7.51 (t, J = 7.7 Hz, IH); 7.18-7.24 (m, IH); 7.12-7.17 (m, IH);

5.42 (t, J = 5.8 Hz, IH); 4.53 (d, J = 5.8 Hz, 2H); 4.45 (s, IH).

Preparation AM: (5)-2-(4-((2,2-dimethyl-l,3-dioxolan-4-yl)methoxy)-

2-fluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane:

A suspension of 3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (0.5 g;

2.1 mmol; commercial), (R)-(2,2-dimethyl-l,3-dioxolan-4-yl)methyl

4-methylbenzenesulfonate (0.6 g; 2.1 mmol; commercial) and K2CO3 (0.58 g; 4.2 mmol) in

DMF (4 mL) was stirred at 100°C overnight. The mixture was cooled to rt and diluted with water (40 mL). The mixture was extracted with EA (3 x 20 mL). The combined org. layers were washed with brine (15 mL), dried over Na2SC>4, filtered and concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a yellow oil which crystallized on standing (0.38 g; 51% yield).

Ή NMR 5 (ίΑ-DMSO) δ: 7.55 (m, IH); 6.75-6.83 (m, 2H); 4.40 (m, IH); 4.06-4.11 (m, 2H); 4.01 (m, IH); 3.74 (dd, J = 6.4, 8.4 Hz, IH); 1.35 (s, 3H); 1.31 (s, 3H); 1.28 (s, 12H).

Preparation AN: 2,2-difluoro-2-(4-iodophenyl)ethan-l-ol:

AN. i. 2-(4-bromophenyl)-2,2-difluoroethan-l-ol:

NaBH4 (0.312 g, 8.24 mmol) was added portion-wise to a solution of ethyl 25 2-(4-bromophenyl)-2,2-difluoroacetate (1.52 g, 5.45 mmol, commercial) in EtOH (50 mL).

The mixture was stirred for 2 h at rt. 17V HC1 (0.5 mL) was added and the resulting mixture was extracted with DCM (2 x 70 mL). The org. layer was washed with brine (70 mL),

- 101 2015226250 05 Nov 2018 dried over Na2SO4, filtered and concentrated to dryness to give the title compound as a white solid (1.21 g, 94% yield).

Ή NMR (ί/s-DMSO) 5: 7.70 (d, J = 8.6 Hz, 2H); 7.47 (d, J = 8.6 Hz, 2H); 5.65 (t, J = 6.4 Hz, 1H); 3.80-3.88 (m, 2H).

MS (ESI, m/z): 242.13 [M+H⁺] for C₈H₇OBrF₂; t_R = 0.75 min.

AN.ii. 2,2-difluoro-2-(4-iodophenyl)ethan-l-ol:

Starting from intermediate AN.i (0.5 g; 2.11 mmol) and proceeding in analogy to Preparation R, step R.iii, the title compound was obtained as a white solid (0.26 g; 43% yield).

Ή NMR (ί/6-DMSO) 5: 7.86 (d, J = 8.5 Hz, 2H); 7.31 (d, J = 8.5 Hz, 2H); 5.63 (t, J = 6.4 Hz, 1H); 3.79-3.86 (m, 2H).

Preparation AO: 3-iodo- V, V-dimethylprop-2-yn-l-amine:

Starting from A,V-dimethylprop-2-yn-l-amine (1 g; 12 mmol; commercial) and proceeding in analogy to Preparation K (56% yield), the title compound was obtained as a yellow solid 15 (0.746 g).

Ή NMR (CDCh) δ: 3.45 (s, 2H); 2.33 (s, 6H).

Preparation AP: (l-(bromoethynyl)cyclopropyl)methyl dimethylglycinate:

AP. i. (I -(bromoethynyl)cyclopropyl)methanol:

To a solution of the compound of Preparation Q (2.4 g; 5.8 mmol) in THF (5.5 mL) was 20 added TBAF (1ΛΤ in THF; 14.5 mL). The resulting solution was stirred at rt for 1 h. The reaction mixture was concentrated in vacuo and the residue purified by CC (Hept-EA) to afford the title compound as a colourless oil (1.01 g; quant.).

Ή NMR (ί/6-DMSO) 5: 4.90 (t, J = 6.0 Hz, 1H); 3.32 (d, J = 6.0 Hz, 2H); 0.77-0.80 (m, 2H); 0.72-0.76 (m, 2H).

AP.ii. (l-(bromoethynyl)cyclopropyl)methyl dimethylglycinate:

Starting from intermediate AP.i (1.01 g, 5.8 mmol) and proceeding in analogy to Preparation AF (coupling: 70% yield), the title product was obtained as a colourless oil (1-07 g)·

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Ή NMR (ζ/ά-DMSO) δ: 3.98 (s, 2H); 3.22 (s, 2H); 2.27 (s, 6H); 0.93-0.98 (m, 2H); 0.88-0. m, 2H).

MS (ESI, m/z): 260.0 [M+H⁺] for CioHi₄N0₂Br; t_R = 0.53 min.

Preparation AQ: (l-(bromoethynyl)cyclopropyl)methyl di-toT-butyl phosphate:

AQ.i. Di-tert-butyl ((l-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl) phosphate:

To a solution of (l-(((ieri-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methanol (13.1 g,

38.5 mmol, prepared as described in WO 2010/135536) in THF (140 mL) at rt was added tetrazole (0.453/ in MeCN; 170 mL) and di-tert-butyl diisopropylphosphoramidite 10 (17.2 mL; 51.8 mmol). The reaction mixture was stirred at 40°C overnight. 35% H2O2 (330 mL) and was added slowly at 0°C over 75 min, keeping the internal temperature below 10°C. After stirring 1 h at 10°C, water (400 mL) was added. The aq. layer was extracted with EA (3 x 100 mL). The combined org. layers were collected, washed with 10% aq. NaHSO3 (5 x 100 mL) and brine (100 mL), dried over MgSO₄, filtered and 15 concentrated to dryness. The residue was purified by CC (Hept-EA) to afford a colourless oil (7.16 g; 35% yield).

Ή NMR (CDCh) δ: 7.62-7.68 (m, 4H); 7.35-7.45 (m, 6H); 3.97 (d, J = 5.5 Hz, 2H);

3.60 (s, 2H); 1.46 (s, 18H); 1.05 (s, 9H); 0.50-0.53 (m, 2H); 0.40-0.44 (m, 2H).

MS (ESI, m/z): 533.10 [M+H⁺] for C₂9H₄₅O₅PSi; t_R = 1.15 min.

AQ.ii. Di-tert-butyl ((l-formylcyclopropyl)methyl)phosphate:

Starting from intermediate AQ.i (7.16 g, 13.4 mmol) and proceeding successively in analogy to Preparation AD, step AD.i (94% yield) and Preparation Y, step Y.iii (85% yield), the title compound was obtained as a colourless oil (3.12 g).

Ή NMR (CDCh) δ: 9.08 (s, 1H); 4.20 (d, J = 6.7 Hz, 2H); 1.48 (s, 18H); 1.20-1.30 (m, 25 4H).

MS (ESI, m/z): 293.00 [M+H⁺] for C13H25O5P; t_R = 0.77 min.

AQ.iii. Di-tert-butyl ((l-ethynylcyclopropyl)methyl)phosphate:

A suspension of intermediate AQ.ii (1 g; 3.44 mmol) and K2CO3 (0.947 g; 6.85 mmol) in MeOH (30 mL) was treated dropwise with dimethyl(l-diazo-2-oxo-propyl)phosphate

- 103 2015226250 05 Nov 2018 (0.992 g, 5.16 mmol). The reaction mixture was stirred at rt overnight. The solvent was evaporated and the residue was dissolved in DCM (30 mL) and water (30 mL). The aq. layer was extracted with EA (20 mL). The combined org. layer were dried over MgSCL, filtered and concentrated to dryness to afford the title compound as a yellow oil (0.93 g, 5 94% yield).

Ή NMR (CDCb) δ: 3.87 (d, J = 6.4 Hz, 2H); 1.90 (s, IH); 1.49 (s, 18H); 0.98-1.01 (m, 2H); 0.88-0.91 (m, 2H).

MS (ESI, m/z): 289.01 [M+H⁺] for C14H25O4P; t_R = 0.85 min.

AQ.iv. (l-(bromoethynyl)cyclopropyl)methyl di-tert-butylphosphate:

To a solution of intermediate AQ.iii (0.93 g, 3.22 mmol) and NBS (0.691 g, 3.88 mmol) in acetone (13 mL) was added AgNCb (0.0586 g, 0.345 mmol). The mixture was stirred at rt for 2.25 h. The reaction mixture was filtered through Celite and the filtrate was concentrated to dryness. The residue was purified by CC (Hept-EA) to give the title compound as a colourless oil (1.07 g, 91% yield).

Ή NMR (CDCb) δ: 3.84 (d, J = 6.3 Hz, 2H); 1.49 (s, 18H); 0.98-1.01 (m, 2H); 0.86-0.88 (m, 2 H)

MS (ESI, m/z): 368.80 [M+H⁺] for Ci₄H₂4O₄BrP; t_R = 0.92 min.

Preparation AR: to'/-butyl((l-((3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan2-yl)phenyl)ethynyl)cyclopropyl)methoxy)diphenylsilane:

To a solution of 2-(2-fluoro-4-iodophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (0.62 g; 1.52 mmol; commercial) in THF (10 mL) were added ieri-butyl((l-ethynylcyclopropyl)methoxy)diphenylsilane (0.507 g; 1.52 mmol; prepared as described in WO 2010/135536), TEA (0.707 mL) and Cui (0.077 g). The mixture was flushed with argon and PdChfPPlbL (0.212 g) was added. The reaction mixture stirred at rt for 2 h. The solvent was removed in vacuo and the residue was purified by CC (Hept-EA) to afford the title compound as a white solid (0.36 g; 43% yield).

Ή NMR (CDCb) δ: 7.70-7.73 (m, 4H); 7.64 (dd, J = 6.5, 7.5 Hz, IH); 7.37-7.46 (m, 6H); 7.14 (dd, J= 1.2, 7.7 Hz, IH); 7.02 (dd, J = 1.1, 10.0 Hz, IH); 3.74 (s, 2H); 1.38 (s, 12H); 1.09 (s, 9H); 0.99-1.02 (m, 2H); 0.92-0.94 (m, 2H).

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Preparation AS: ((l-(bromoethynyl)cyclobutyl)methoxy)(toT-butyl)diphenylsilane:

Starting from cyclobutane- 1,1-diyldimethanol (3.03 g; 24.8 mmol; commercial) and proceeding successively in analogy to Preparation Y, steps Y.ii (98% yield), Y.iii (86% yield), Y.iv (93% yield) and Y.v (quant.), the title compound was obtained as a 5 colourless oil (4.79 g).

Ή NMR (CDCh) δ: 7.70-7.74 (m 4H); 7.40-7.48 (m, 6H); 3.67 (s, 2H); 2.18-2.29 (m, 4H); 2.00-2.08 (m, 1H); 1.86-1.95 (m, 1H); 1.11 (s, 9H).

Preparation AT: ((3-(bromoethynyl)oxetan-3-yl)methoxy)(toT-butyl)diphenylsilane:

AT.i. 3-(((tert-butyldiphenylsilyl)oxy)methyl)oxetane-3-carbaldehyde:

Starting from oxetane-3,3-diyldimethanol (5 g; 42.3 mmol; commercial) and proceeding successively in analogy to Preparation Y, steps Y.ii (95% yield) and Y.iii (90% yield), the title compound was obtained, after purification by CC (Hept-EA), as a colourless oil (12.87 g).

Ή NMR (i/₆-DMSO) 5: 9.82 (s, 1H); 7.59-7.62 (m, 4H); 7.44-7.50 (m, 6H); 4.66 (d, 15 J = 6.3 Hz, 2H); 4.43 (d, J = 6.3 Hz, 2H); 4.15 (s, 2H); 0.98 (s, 9H).

AT. ii. ((3-(bromoethynyl)oxetan-3-yl)methoxy)(tert-butyl)diphenylsilane:

Starting from intermediate AT.i (2 g; 5.64 mmol) and proceeding successively in analogy to Preparation AQ, steps AQ.iii (87% yield) and AQ.iv (98% yield), the title compound was obtained, after purification by CC (Hept-EA), as a colourless oil (0.24 g).

Ή NMR (i/₆-DMSO) 5: 7.64-7.72 (m, 4H); 7.42-7.54 (m, 6H); 4.60 (d, J = 5.9 Hz, 2H); 4.48 (d, J = 5.9 Hz, 2H); 3.92 (s, 2H); 1.03 (s, 9H).

Preparation AU: (((1R*,2R*)-2-(bromoethyny 1)2-fluorocyclopropyl)methoxy)(ti'/7-butyl)diphenylsilane:

AU. i. ((1 R*,2R*)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-l-fluorocyclopropyl)methanol:

To a solution of ethyl (1R*, 2R*)-2-(((ieri-butyldiphenylsilyl)oxy)methyl)-

1-fluorocyclopropane-1-carboxylate (0.5 g; 1.25 mmol; prepared as described in Sakagami et al., Bioorg. Med. Chem. (2008), 16(8), 4359-4366) in THF (9 mL), cooled to -78°C, was added dropwise LiBH4 (2M in THF; 2.2 mL; 4.4 mmol). The reaction mixture was allowed

- 105 2015226250 05 Nov 2018 to reach rt and stirred at rt for 24 h. MeOH (2 mL) was carefully added, the reaction mixture was stirred for 20 min, concentrated to dryness and partitioned between water (10 mL) and DCM (15 mL). The aq. layer was extracted with DCM (2 x 10 mL). The combined org. layers were dried over Na2SC>4 and filtered. After concentration of the 5 filtrate to dryness, the title compound was obtained as a colourless oil (0.429 g; 96% yield).

Ή NMR (CDCh) δ: 7.66-7.72 (m, 4H); 7.36-7.45 (m, 6H); 3.89 (ddd, J= 1.6, 6.0, 11.0 Hz, IH); 3.80-3.83 (m, IH); 3.70-3.78 (m, 2H); 1.74 (t, J = 6.4 Hz, IH);

1.24-1.33 (m, IH); 1.05 (s, 9H); 0.79-0.88 (m, 2H).

MS (ESI, m/z): 358.95 [M+H⁺] for C2iH₂7O₂FSi; t_R = 1.01 min.

A U. ii. (((1R*,2R*)-2-(bromoethynyl)-

2-fluorocyclopropyl)methoxy)(tert-butyl)diphenylsilane:

Starting from intermediate AU.i (2.04 g; 5.7 mmol) and proceeding successively in analogy to Preparation Y, steps Yiii (83% yield), Y.iv (17% yield) andY.v (99% yield), 15 the title compound was obtained as a brown oil (0.351 g).

Ή NMR (CDCh) δ: 7.66-7.70 (m 4H); 7.36-7.45 (m, 6H); 3.84 (ddd, J = 1.6, 5.8, 11.3 Hz, IH); 3.71 (ddd, J= 1.1, 8.0, 11.3 Hz, IH); 1.56-1.64 (m, IH); 1.14-1.20 (m, IH); 1.06 (s, 9H); 0.98-1.04 (m, IH).

Preparation AV: (((//? *,2R *)-2-(bromoethynyl)20 l-fluorocyclopropyl)methoxy)(ti'/7-butyl)diphenylsilane:

AV.i. ((lR*,2R*)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-l-fluorocyclopropyl)methyl acetate:

To a solution of intermediate AU.i (1.5 g, 4.19 mmol) in THF (25 mL) was added TEA (1.6 mL, 11.5 mmol). AcCl (0.62 mL, 8.51 mmol) was added dropwise over 5 min at 0°C.

The reaction mixture was stirred at 0°C for 1 h. The reaction mixture was poured onto water (40 mL) and the aq. layer was extracted with EA (3 x 40 mL). The combined org. layers were dried over MgSCU and the solvent was removed under reduce pressure to give the crude product as a yellow oil (2.18 g).

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Ή NMR (CDCh) δ: 7.66-7.71 (m, 4H); 7.36-7.45 (m, 6H); 4.27-4.35 (m, 2H); 3.90 (ddd, J= 1.6, 5.8, 11.0 Hz, IH); 3.69 (ddd, J = 1.2, 8.3, 11.0 Hz, 1H);2.11 (s, 3H); 1.31-1.40 (m, IH); 1.06 (s, 9H); 0.80-0.94 (m, 2H).

MS (ESI, m/z): 400.98 [M+H⁺] for Ci₂Hi₈NO₂; t_R = 1.09 min.

AV.ii. ((lR*,2R*)-l-fluoro-2-(hydroxymethyl)cyclopropyl)methyl acetate:

To a solution of intermediate AV.i (2.16 g; 5.39 mmol) in THF (10 mL) was added TBAF (\M in THF; 7 mL). The reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated in vacuo and purified by CC (DCM-MeOH) to afford the title alcohol as a yellow oil (0.726 g; 83% yield).

‘HNMR (CDCh) δ: 4.27-4.41 (m, 2H); 3.94 (m, IH); 3.64 (m, IH); 2.13 (s, 3H); 1.51 (m, IH); 1.41 (m, IH); 0.98-1.06 (m, 2H).

A V. Hi. ((1 R*,2R*)-2-ethynyl-l-fluorocyclopropyl)methanol:

Starting from intermediate AV.ii (0.62 g; 3.8 mmol) and proceeding successively in analogy to Preparation Y, step Y.iii (100% yield) and Preparation AQ, step AQ.iii (100% yield), the title compound was obtained as a colourless oil (0.25 g).

Ή NMR (CDCh) δ: 3.86 (d, J = 2.5 Hz, IH); 3.82 (d, J = 2.8 Hz, IH); 2.00 (d, J = 2.2 Hz, IH); 1.61 (ddt, J = 2.1, 7.1, 10.2 Hz, IH); 1.37 (ddt, J = 0.7, 7.0, 19.4 Hz, IH); 1.21 (ddd, J = 6.9, 10.2, 11.3 Hz, IH).

A V. iv. Tert-butyl(((1R,2R)-2-ethynyl-l-fluorocyclopropyl)methoxy)diphenylsilane:

To a solution of intermediate AV.iii (0.232 g, 2.0 mmol) in DCM (4.1 mL) was added imidazole (0.28 g; 4.1 mmol). The solution was cooled to 0°C and TBDPSC1 (0.55 mL;

2.1 mmol) was added dropwise. The reaction mixture was stirred at rt for 2 h. 10% aq. NaHSCL (6 mL) was added and the phases were separated. The aq. layer was extracted with DCM (10 mL). The combined org. layers were dried over MgSCL, filtered and evaporated under reduced pressure. The residue was purified by CC (Hept-EA) to afford the title product as a colourless oil (0.45 g; 63% yield).

Ή NMR (500 MHz, CDCh) δ: 7.63-7.67 (m, 4H); 7.37-7.47 (m, 6H); 3.91 (m, 2H);

1.97 (d, J = 2.2 Hz, IH); 1.58 (m, IH); 1.29 (m, IH); 1.18 (m, IH); 1.05 (s, 9H).

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AKv. ((( 1R*,2R*)-2-(bromoethynyl)-

1-fluorocyclopropyl) methoxy) (tert-butyl) diphenylsilane:

Starting from intermediate AV.iv (0.45 g; 1.28 mmol) and proceeding in analogy to

Preparation AQ, step AQ.iv, the title compound was obtained as a colourless oil (0.32 g; 5 58% yield).

Ή NMR (CDCh) δ: 7.62-7.67 (m, 4H); 7.37-7.48 (m, 6H); 3.89 (dd, J = 1.0, 14.3 Hz, 2H);

1.57 (m, IH); 1.27 (m, IH); 1.16 (m, IH); 1.05 (s, 9H).

Preparation AW: (/?5)-((4-bromo-2-cyclobutylbut-3-yn- l-yl)oxy)(ti'/7-butyl)dimethylsilane:

AW.i. (RS)-2-cyclobutyl-3-hydroxypropyl acetate:

To a solution of 2-cyclobutylpropane-l,3-diol (4.170 g; 32 mmol) and camphor10-sulfonic acid (0.149 g; 0.641 mmol) in DCM (60 mL) was added trimethylorthoacetate (16.3 mL, 128 mmol). The mixture was stired for 2 h at rt. The solvent was evaporated and 50% aq. AcOH (55 mL; 480 mmol) was added. The reaction mixture was stirred at rt for 15 3 h. The solvent was evaporated and the residue was dissolved in TBME (60 mL), washed with sat. aq. NaHCO3 (50 mL) and brine (50 mL), dried over MgSO4 and filtered. After concentration to dryness, the title compound was obtained as a yellowish oil (5.210 g; 94% yield).

Ή NMR (CDCh) δ: 4.20 (dd, J = 4.0, 11.3 Hz, IH); 4.06 (dd, J = 6.8, 11.3 Hz, IH); 20 3.59 (dd, J = 3.8, 11.3 Hz, IH); 3.45 (dd, J = 6.5, 11.3 Hz, IH); 2.23-2.35 (m, IH);

2.02-2.13 (m, 2H, overlapped); 2.09 (s, 3H); 1.86-1.97 (m, IH); 1.73-1.85 (m, 4H).

A W. ii. (RS)-3-((tert-butyldimethylsilyl)oxy)-2-cyclobutylpropyl acetate:

To a solution of intermediate AW.i (5.210 g; 30.3 mmol) in DCM (50 mL) was added imidazole (4.119 g; 60.5 mmol) and TBDMS-C1 (5.280 g; 33.3 mmol). After stirring for 25 3 h, water (40 mL) was added. The two phases were separated and the aq. layer was extracted with DCM (2 x 50 mL). The combined org. layers were dried over MgSCfi, filtered and concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a colourless oil (7.417 g; 86% yield).

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Ή NMR (CDCh) δ: 4.01-4.08 (m, 2H); 3.59 (dd, J = 4.0, 10.0 Hz, IH); 3.49 (dd, J = 6.0, 10.0 Hz, IH); 2.26-2.36 (m, IH); 1.99-2.08 (m, 2H, overlapped); 2.05 (m, 3H); 1.83-1.93 (m, IH); 1.71-1.83 (m, 4H); 0.87-0.92 (m, 9H); 0.02-0.05 (m, 6H).

MS (ESI, m/z): 287.09 [M+H⁺] for C15H30O3S1; t_R = 1.10 min.

AW.iii. (RS)-((4-bromo-2-cyclobutylbut-3-yn-l-yl)oxy)(tert-butyl)dimethylsilane:

Starting from intermediate AW.ii (7.4 g; 25.9 mmol), and proceeding successively in analogy to Preparation AE, stepAE.iii (91% yield) and Preparation Y, steps Y.iii to Y.v (85% yield over the 3 steps), the title compound was obtained as a colourless oil (3.23 g).

Ή NMR (CDCh) δ: 3.59 (dd, J = 6.0, 9.7 Hz, IH); 3.52 (dd, J = 6.6, 9.7 Hz, IH); 10 2.54-2.60 (m, IH); 2.46-2.54 (m, IH); 1.97-2.05 (m, 2H); 1.77-1.96 (m, 4H); 0.90-0.94 (m,

9H); 0.06-0.10 (m, 6H).

Preparation AX: ((IS^SJ-l-Ojromoethynylj-l-methylcyclopropyljmethyl acetate:

AX.i. (R,E)-3-(2,2-dimethyl-l,3-dioxolan-4-yl)-2-methylallyl acetate:

To a solution of (R,£)-3-(2,2-dimethyl-l,3-dioxolan-4-yl)-2-methylprop-2-en-l-ol (1.4 g;

8.1 mmol; prepared as reported in Smith III et al., Tetrahedron (2009), 65(33), 6470-6488) in THF (48 mL) was added TEA (2.8 mL; 20.1 mmol). Then AcCl (1.2 mL; 16.5 mmol) was added dropwise over 10 min at 0°C. The reaction mixture was stirred at 0°C for 2 h. The reaction mixture was poured into water (80 mL) and extracted with EA (3 x 50 mL). The combined org. layers were dried over MgSCU, filtered and the filtrate removed under reduce pressure. The crude product was purified by CC (PE-EA) to afford the title compound as a colourless oil (1.64 g; 94% yield).

Ή NMR (CDCh) δ: 5.48-5.51 (m, IH); 4.79-4.84 (m, IH); 4.44-4.52 (m, 2H); 4.07-4.11 (m, IH); 3.55 (t, J = 8.0 Hz, IH); 2.09 (s, 3H); 1.75 (d, J= 1.3 Hz, 3H); 1.43 (s, 3H); 1.40 (s, 3H).

AX. ii. ((IS,2S)-2-((R)-2,2-dimethyl-l,3-dioxolan-4-yl)-l-methylcyclopropyl)methyl acetate:

To a mechanically stirred solution of intermediate AX.i (1.64 g; 7.65 mmol) in toluene (102 mL), cooled to -25°C, was added dropwise ZnEt₂ (15% in toluene; 34.5 mL;

38.3 mmol) over 20 min, keeping IT below -20°C. Then diiodomethane (6.5 mL;

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79.9 mmol) was added dropwise over 10 min, keeping IT below -20°C. The reaction mixture was stirred at -20°C for 2 h, then allowed to slowly warm up to rt and stirred overnight. The reaction mixture was quenched with sat. aq. NH4CI (33 mL) and extracted with Et20 (4 x 30 mL). The combined org. layers were washed with sat. aq. Na2S2Ch (30 mL), water (30 mL) and brine (30 mL), then dried over MgSCh and filtered. After evaporation of the filtrate under reduced pressure, a yellow oil (22.4 g) was obtained. The crude product was purified by CC (PE-EA) to afford the title compound as a colourless oil (1.4 g; 80% yield).

Ή NMR (CDCh) δ: 4.09 (dd, J = 5.9, 7.9 Hz, 1H); 3.89 (d, J =11.3 Hz, 1H); 3.77 (d, 10 J = 11.3 Hz, 1H); 3.70-3.76 (overlapped m, 1H); 3.61-3.66 (m, 1H); 2.07 (s, 3H); 1.45 (s,

3H); 1.36 (s, 3H); 1.13 (s, 3H); 0.85-0.95 (m, 2H); 0.56 (t, J = 5.0 Hz, 1H).

AX. Hi. ((IS,2S)-2-((R)-l,2-dihydroxyethyl)-l-methylcyclopropyl)methyl acetate:

A mixture of intermediate AX.ii (1.4 g; 6.1 mmol) in AcOH (80%; 14 mL) was stirred at rt for 23 h. The mixture was added to sat. aq. NaHCO3 (100 mL; pH 6-7) and the aq. layer was extracted with DCM (3 x 60 mL). The combined org. layers were washed with water (10 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated to dryness. The residue was co-evaporated with cyclohexane. The crude was purified by CC (DCMMeOH) to afford the title compound as a colourless oil (1 g: 87% yield).

Ή NMR (CDCh) δ: 3.89 (d, J =11.3 Hz, 1H); 3.74 (d, J= 11.3 Hz, 1H); 3.68 (dd, 20 J = 3.4, 11.2 Hz, 1H); 3.57 (dd, J = 7.4, 11.2 Hz, 1H); 3.33-3.39 (m, 1H); 2.07 (s, 3H);

1.16 (s, 3H); 0.89 (td, J = 5.7, 9.0 Hz, 1H); 0.80 (dd, J = 4.9, 8.8 Hz, 1H); 0.48 (t, J = 5.3 Hz, 1H).

AX.iv. ((lS,2S)-2-formyl-l-methylcyclopropyl)methyl acetate:

To a solution of intermediate AX.iii (1 g; 5.3 mmol) in THF (16.5 mL), water (3.4 mL) and 25 sat. aq. NaHCCh (1.6 mL), cooled to 0°C, was added NalCh (1.48 g; 6.9 mmol). The reaction mixture was stirred at 0°C for 30 min, then filtered and washed with Et2O. The aq. layer was extracted with Et2O (3 x 40 mL). The combined org. layers were dried over

MgSCU, filtered and concentrated to dryness. The title compound was obtained as a colourless oil (0.81 g; 98% yield).

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Ή NMR (CDCh) δ: 9.47 (d, J = 4.7 Hz, 1H); 4.00 (d, J =11.4 Hz, 1H); 3.85 (d, J = 11.4 Hz, 1H); 2.09 (s, 3H); 1.92-1.97 (m, 1H); 1.39 (t, J = 5.3 Hz, 1H); 1.32 (s, 3H); 1.21 (dd, J = 5.0, 8.3 Hz, 1H).

AX. v. ((lS,2S)-2-(bromoethynyl)-l-methylcyclopropyl)methyl acetate:

Starting from intermediate AX.iv (0.81 g; 5.19 mmol) and proceeding successively in analogy to Preparation P, steps P.i (81% yield) and P.ii (62% yield), the title compound was obtained, after purification by CC (PE/TBME), as a colourless oil (0.6 g).

Ή NMR (CDCh) δ: 3.89 (d, J = 11.4 Hz, 1H); 3.80 (d, J = 11.4 Hz, 1H); 2.07 (s, 3H);

1.39 (dd, J = 5.5, 8.9 Hz, 1H); 1.27 (s, 3H); 0.94 (dd, J = 4.8, 8.9 Hz, 1H); 0.65 (t, 10 J = 5.1 Hz, 1H).

Preparation AY: l-(3-(bromoethynyl)azetidin-l-yl)-2-hydroxyethan-l-one:

AY. i. Tert-butyl 3-(bromoethynyl)azetidine-l-carboxylate:

Starting from Ze/7-butyl 3-ethynylazetidine-1 -carboxylate (0.5 g; 2.76 mmol; prepared as described in WO 2014/165075), and proceeding in analogy to Preparation AQ, step AQ.iv, 15 the title compound was obtained, after purification by CC (Hex-TBME), as a colourless oil (0.673 g, 94% yield).

Ή NMR (CDCh) δ: 4.14 (m, 2 H), 3.96 (dd, J = 6.3 Hz, 8.4 Hz, 2 H), 3.34 (m, 1 H), 1.46 (s, 9 H).

AY.ii. 3-(bromoethynyl)azetidine hydrochloride:

Starting from the intermediate AY.i (0.670 g, 2.7 mmol) and proceeding in analogy to Preparation AG, step AG.ii, the title compound was obtained, after trituration in Et₂O, as an off-white solid (0.49 g; 97% yield).

Ή NMR (CDCh) δ: 9.10-9.44 (m, 2H), 4.06-4.15 (m, 2H), 3.87-3.96 (m, 2H), 3.74 (m, 1H).

MS (ESI, m/z): 162.0 [M+H⁺] for C₅H₆NBr; t_R = 0.23 min.

AY.iii. l-(3-(bromoethynyl)azetidin-l-yl)-2-hydroxyethan-l-one:

To a solution of intermediate AY.ii (0.49 g; 2.48 mmol) in DMF (5 mL) were added successively HOBT (0.7 g; 5.05 mmol), TEA (1.21 mL; 8.69 mmol), glycolic acid (0.2 g;

2.63 mmol) and EDC (0.85 g; 4.38 mmol). The reaction mixture was diluted with DMF

- Ill 2015226250 05 Nov 2018 (4 mL) and the reaction mixture was stirred at 60°C for 90 min. The solvent was removed in vacuo and the residue was partitionned between brine (20 mL) and EA-MeOH (9-1;

mL). The aq. layer was extracted with EA-MeOH (9-1; 4 x 20 mL). The org. layer was dried over Na2SC>4, filtered and concentrated to dryness. The residue was purified by CC (Hept-EA) to afford a the title compound (0.32 g, 60% yield) as an off-white solid.

Ή NMR (ί/6-DMSO) 5: 4.97 (t, J = 6.1 Hz, 1H); 4.40 (t, J = 8.7 Hz, 1H); 4.11 (m, 2H), 3.89 (d, J = 6.0 Hz, 2H); 3.77 (dd, J = 6.2, 9.0 Hz, 1H); 3.55 (m, 1H).

MS (ESI, m/z): 220.1 [M+H⁺] for C₇H₈NO₂Br; t_R = 0.48 min.

Preparation AZ: 3-(3-iodoprop-2-yn-l-yl)oxetan-3-ol:

A flask charged with ZnBiy (1.08 g, 4.80 mmol) and Mg turnings (5.85 g) was heated with stirrring under vacuum at 150°C for 2 h and then cooled to rt. Et2O (90 mL) and a few drops of 1,2-dibromoethane were added. Propargyl bromide (9 mL; 118.78 mmol) in Et2O (70 mL) was then added dropwise. The mixture was stirred at the same temperature for 1 h.

In a separate flask were introduced 3-oxetanone (3.15 g; 43.71 mmol) and THE (420 mL).

The Grignard reagent solution (127 mL; 65.56 mmol), cannulated in a graduated addition funnel, was added dropwise. The solution was stirred at the same temperature for 1 h and diluted with sat. aq. NH4CI and Hex (100 mL). The two layers were separated and the aq. layer was extracted with Hex (100 mL). The combined org. layers were dried over MgSCL, filtered and concentrated under reduced pressure. Starting from the crude intermediate thus obtained (4.33 g; 38.63 mmol) and proceeding in analogy to Preparation K, the title compound was obtained as a yellow solid (3.01 g; 33% yield).

Ή NMR (CDCh) δ: 4.51 (d, J = 7.4 Hz, 2H); 4.66 (d, J = 7.1 Hz, 2H); 2.98 (s, 2H);

2.55 (s, 1H).

Preparation BA: 4-(iodoethynyl)tetrahydro-2Z7-pyran-4-ol:

Starting from 4-ethynyltetrahydro-2Z/-pyran-4-ol (1.17 g; 9.33 mmol; commercial) and proceeding in analogy to Preparation K, the title iodide was obtained, after purification by CC (Hept-EA), as a yellowish solid (1.57 g, 67% yield).

‘HNMR (ί/6-DMSO) 5: 5.64 (s, 1H); 3.64-3.74 (m, 2H); 3.40-3.51 (m, 2H); 1.68-1.79 (m, 2H); 1.51-1.62 (m, 2H).

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Preparation BB: (3/?,65)-6-(bromoethynyl)tetrahydro-2Z7-pyran-3-amine hydrochloride:

Starting from Ze/7-butyl ((3/?,65j-6-fbrmyltctrahydro-2//-pyran-3-yl)carbamatc (3.1 g;

13.6 mmol, prepared as described in Surivet et al., J. Med. Chem. (2013), 56, 7396-7415) and proceeding successively in analogy to Preparation P, step P.i (68% yield), Preparation Y, step Y.v (97% yield) and Preparation AG, step AG.ii (89% yield), the title compound was obtained, after final trituration in diethyl ether, as a white solid (0.353 g).

Ή NMR (ί/ή-DMSO) 5: 8.21-8.38 (m, 3H); 4.41 (dd, J = 3.2, 7.4 Hz, 1H); 3.97 (dd, J = 3.2, 11.6 Hz, 1H); 3.45 (dd, J = 7.4, 11.6 Hz, 1H); 3.17 (m, 1H); 1.98-2.08 (m, 2H);

1.55-1.72 (m, 2H).

Preparation BC: l-(5-ethynylthiophen-2-yl)cyclopropan-l-amine:

Starting from l-(5-bromothiophen-2-yl)cyclopropan-l-amine hydrochloride (0.299 g;

1.17 mmol; commercial) and proceeding in analogy to Procedure C (84% yield) and Preparation H, step H.ii (74% yield), the title compound was obtained, after purification by

CC (DCM-MeOH containing 1% aq. NH₄OH), as a yellowish oil (0.118 g).

Ή NMR (ί/6-DMSO) 5: 7.13 (d, J = 3.7 Hz, 1H); 6.64 (d, J = 3.7 Hz, 1H); 4.42 (s, 1H);

2.58 (s, 2H); 1.05-1.08 (m, 2H); 0.94-0.97 (m, 2H).

Preparation BD: 3-(4-iodophenyl)oxetan-3-amine hydrochloride:

BD.i. N-(3-(4-iodophenyl)oxetan-3-yl)-2-methylpropane-2-sulfinamide:

BuLi (1.1Λ7 in hexanes; 11.4mL) was added dropwise to a solution of 1,4-iodobenzene (4.36 g) in THF (50 mL) at -78°C. After stirring for 1 h, a solution of 2-methyl-TV-oxetan-

3-ylidenepropane-2-sulfinamide (1.64 g; commercial) in THF (10 mL) was added dropwise over the course of 30 min at -78°C. The reaction mixture was gradually warmed to rt. After 1 h, sat. aq. NH4CI was added and the aq. layer was extracted with EA. The combined org. layer was washed with sat. aq. NaHCCh and brine, dried over Na2SO₄, filtered and concentrated to dryness. The residue was purified by CC (EA-Hept) to give the title compound as a colourless oil (0.751 g; 21% yield).

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Ή NMR (ζ/ά-DMSO) δ: 7.77 (d, J = 8.4 Hz, 2H); 7.30 (d, J = 8.4 Hz, 2H); 6.35 (s, 1H); 4.98 (d, J = 6.3 Hz, 1H); 4.90-4.94 (m, 1H); 4.85-4.88 (m, 1H); 4.67 (d, J = 6.3 Hz, 1H); 1.11 (s, 9H).

MS (ESI, m/z): 379.97 [M+H⁺] for Ci₃Hi₈NO₂IS; t_R = 0.78 min.

BD.ii. 3-(4-iodophenyl)oxetan-3-amine hydrochloride:

To a solution of intermediate BD.i (0.751 g; 1.98 mmol) in DCM (20 mL) was added a 4M solution of HCI in dioxane (1.06 mL). After stirring for 30 min at rt, the solids were filtered off and washed with Hex (3 mL) to afford the title compound as a white solid (0.624 g; 100% yield)

Ή NMR (ί/6-DMSO) 5: 9.14-9.30 (m, 3H); 7.82-7.90 (m, 2H); 7.34-7.40 (d, J = 8.5 Hz, 2H); 4.80-5.00 (m, 4H).

MS (ESI, m/z): 299.89 [M+Na⁺] for C9H10NOI; t_R = 0.50 min.

Preparation BE: (3-(4-iodophenyl)oxetan-3-yl)methanol:

Starting from (3-(4-bromophenyl)oxetan-3-yl)methanol (0.24 g; 0.98 mmol; commercial) 15 and proceeding in analogy to Preparation R, step R.iii, the title iodide was obtained, after purification by CC (Hept-EA), as an off-white solid (0.27 g, 94% yield).

Ή NMR (ί/6-DMSO) 5: 7.69 (d, J = 7.1 Hz, 2H); 6.96 (d, J = 7.1 Hz, 2H); 5.10 (t, J = 5.6 Hz, 1H); 4.60-4.73 (m, 4H); 3.69 (d, J = 5.3 Hz, 2H).

Preparation BF: l-(4-iodophenyl)cyclopropan-l-amine hydrochloride:

BF.i. Tert-butyl (l-(4-iodophenyl)cyclopropyl)carbamate:

Starting from Ze/7-butyl (l-(4-bromophenyl)cyclopropyl)carbamate (0.502 g; 1.61 mmol; commercial) and proceeding in analogy to Preparation R, step R.iii, the title iodide was obtained as a brown solid (0.53 g, 92% yield).

'HNMR (ί/6-DMSO) 5: 7.71 (s, 1H); 7.61 (d, J = 8.4 Hz, 2H); 6.93 (d, J = 8.4 Hz, 2H);

1.37 (s, 9H); 1.11 (s, 2H); 1.09 (s, 2H).

MS (ESI, m/z): 360.0 [M+H⁺] for Ci₄HisNO₂I; t_R = 0.94 min.

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BF. ii. l-(4-iodophenyl)cyclopropan-l-amine hydrochloride:

Intermediate BF.i (0.347 g; 0.966 mmol) was stirred at rt for 3 h in a HC1 solution (4Λ7 in dioxane; 3 mL). Et20 was added (5 mL) and the precipitate was filtered, washed with ether (2 mL) and dried to afford the title compound as a brown solid (0.231 g; 81% yield).

Ή NMR (ί/6-DMSO) δ: 8.93 (s, 2H); 7.78 (d, J = 8.4 Hz, 2H); 7.23 (d, J = 8.4 Hz, 2H);

1.37-1.44 (m, 2H); 1.16-1.23 (m, 2H).

Preparation BG: cis-3-(hydroxymethyl)-l-(3-iodoprop-2-yn-l-yl)cyclobutan-l-ol:

BG. i. Cis-3-(((tert-butyldiphenylsilyl)oxy)methyl)-l-(3-(trimethylsilyl)prop-2-yn- l-yl)cyclobutan-l-ol:

To a solution of 3-(((/erAbutyldiphenylsilyl)oxy)methyl)cyclobutan-l-one (2 g;

3.54 mmol; prepared as described in WO 2006/063281) in dry THF (5.9 mL) at rt under nitrogen atmosphere, was added a solution of trimethyl(3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)prop-l-yn-l-yl)silane (1.27 g; 5.32 mmol; commercial) in dry THF (5.9 mL) followed by ZnEt2 (15% in toluene; 0.73 mL; 1.06 mmol). The reaction mixture was stirred at rt for 4 h. Water (10 mL) was added carefully followed by aq. HC1 (6/V/; 0.3 mL) and the reaction was stirred for 15 min. The mixture was extracted with EA (3 x 15 mL). The combined org. layers were washed with brine (15 mL), dried over Na2SC>4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by CC (Hept-EA) to afford the desired product as a colourless oil (2 g; quant.).

Ή NMR (ί/6-DMSO) 5: 7.59-7.63 (m, 4H); 7.41-7.49 (m, 6H); 5.09 (s, 1H); 3.62 (d, J = 6.8 Hz, 2H); 2.31 (s, 2H); 1.88-1.99 (m, 3H); 1.22-1.31 (m, 2H); 1.00 (s, 9H); 0.07 (s, 9H).

MS (ESI, m/z): 451.0 [M+H⁺] for C₂7H38O₂Si2; t_R = 1.14 min.

BG.ii. Cis-3-(hydroxymethyl)-l-(3-iodoprop-2-yn-l-yl)cyclobutan-l-ol:

Starting from intermediate BG.i (crude; 2 g; 1.77 mmol) and proceeding successively in analogy to Preparation AD, step AD.ii (72% yield) and Preparation K (48% yield), the title compound was obtained, after purification by CC (Hept-EA), as a yellow oil (0.4 g) which crystallized.

'HNMR (ί/6-DMSO) 5: 5.06 (s, 1H); 4.45 (t, J = 5.4 Hz, 1H); 3.32-3.36 (overlapped m,

2H); 2.48-2.52 (overlapped m, 1H); 1.98-2.04 (m, 2H); 1.88 (m, 1H); 1.64-1.70 (m, 2H).

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MS (ESI, m/z): 266.95 [M+H⁺] for C₈HnO₂I; t_R = 0.52 min.

Preparation BH: ((di-ter/-butoxyphosphoryl)oxy)methyl (l-(iodoethynyl)cyclopropyl)carbamate:

BH.i. Chloromethyl (l-(iodoethynyl)cyclopropyl)carbamate:

To a solution of the compound of Preparation AG (0.134 g; 0.48 mmol) and l,8-bis(dimethylamino)naphthalene (0.321 g; 1.5 mmol) in DCM (9.5 mL) was added chloromethyl chloroformate (0.05 mL; 0.56 mmol). The mixture was stirred at rt for 1 h. Water (10 mL) was added, the phases were separated and the aq. layer was extracted with DCM (10 mL). The combined org. layers were washed with water (5 mL) and brine 10 (10 mL), dried over MgSCU and concentrated under reduced pressure. The residue was purified by CC (Hept-EA) to afford the title compound as a yellowish oil (0.111 g; 77% yield).

Ή NMR (CDCh) δ: 5.68-5.81 (m, 2H); 5.41 (m, 1H); 1.28-1.31 (m, 2H); 1.16-1.20 (m, 2H).

BH.ii. ((Di-tert-butoxyphosphoryl)oxy)methyl (l-(iodoethynyl)cyclopropyl)carbamate:

To a solution of intermediate BH.i (0.111 g; 0.37 mmol) in DME (5.5 mL) was added tetra-n-butylammonium di-ieri-butylphosphate (0.237 g; 0.53 mmol). The reaction mixture was heated at 80°C for 2.5 h. Water (10 mL) was added and the mixture was extracted with EA (10 mL). The combined org. layers were washed with water (2x5 mL) and brine 20 (5 mL), dried over MgSCU and concentrated to dryness to afford the title compound as a brown gum (0.133 g; 76% yield).

Ή NMR (CDCh) δ: 3.54 (s, 1H); 3.40 (s, 2H); 1.49 (s, 18H); 1.24-1.30 (m, 2H); 1.12-1.16 (m, 2H).

MS (ESI, m/z): 473.9 [M+H⁺] for CisH^NOelP; t_R = 0.85 min.

Preparation BI: 2-(5-ethynylthiazol-2-yl)propan-2-ol:

Starting from 2-(5-bromothiazol-2-yl)propan-2-ol (0.429 g, 1.87 mmol; commercial) and proceeding in analogy to Procedure C (Sonogashira coupling, 76% yield) and Preparation H. step H.ii (TMS cleavage, 68% yield), the title compound was obtained, after purification by CC (Hept-EtOAc), as an yellowish solid (0.118 g).

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Ή NMR (ί/6-DMSO) δ: 7.91 (s, 1H); 6.15 (s, 1H); 4.68 (s, 1H); 1.48 (s, 6H).

MS (ESI, m/z): 168.00 [M+H⁺] for CsHgNOS; t_R = 0.62 min.

Preparation BJ: ((1R,2/?)-2-(bromoethynyl)-l-fluorocyclopropyl)methyl benzoate and ((15,25)-2-(bromoethynyl)-l-fluorocyclopropyl)methyl benzoate:

BJ. i. ((1 R*,2R*)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-l-fluorocyclopropyl)methyl benzoate:

To a solution of intermediate AU.i (5.51 g, 15.4 mmol) in THF (93 mL) was added TEA (6 mL; 43.1 mmol). Benzoyl chloride (3.6 mL; 30.7 mmol) was added dropwise over 2 min at 0°C. The reaction mixture was stirred at 0°C for 5 h before being poured onto water (75 mL). The aq. layer was extracted with EA (3 x 50 mL). The combined org. layers were dried over MgSCU and concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a colourless oil (6.49 g; 91% yield).

Ή NMR (500 MHz, CDCh) δ: 8.09-8.12 (m, 2H); 7.67-7.70 (m, 4H); 7.56 (m, 1H); 7.40-7.44 (m, 4H); 7.35-7.38 (m, 4H); 4.62 (m, 1 H); 4.51 (ddd, J= 1.1, 13.0, 23.8 Hz,

1H); 3.93 (ddd, J = 1.5, 5.6, 11.0 Hz, 1H); 3.70 (ddd, J = 1.1, 8.4, 10.9 Hz, 1H); 1.46 (m,

1H); 1.30 (m, 1H); 1.02 (s, 7H); 0.97 (m, 1H); 0.84-0.91 (m, 2H).

MS (ESI, m/z): 463.07 [M+H⁺] for C₂8H3iO₃FSi; t_R = 1.14 min.

BJ.ii. ((lR,2R)-2-(2,2-dibromovinyl)-l-fluorocyclopropyl)methyl benzoate and ((lS,2S)-2-(2,2-dibromovinyl)-l-fluorocyclopropyl)methyl benzoate:

Starting from intermediate BJ.i (6.49 g; 14 mmol) and proceeding successively in analogy to Preparation AP, stepAP.i (89% yield), Preparation Y, step Y.iii (84% yield) and Y.iv (adding 2 eq. TEA, 96% yield), a mixture of enantiomers (2.71 g) was obtained. After separation by chiral prep-HPLC (Method C) (Hept-EtOH 3-7; flow rate: 16 mL/min, UV detection at 224 nM), the title enantiomers (the absolute stereochemistries of which have not been assigned) were obtained as white solids (1.25 g each); their respective retention times (measured under same conditions as analytical LC-MS except that the flow rate is 0.8 mL/min) were 5.3 and 7.0 min.

Ή NMR (ί/6-DMSO) 5: 7.99-8.01 (m, 2H); 7.69 (m, 1H); 7.54-7.58 (m, 2H); 6.38 (dd, J = 1.4, 8.9 Hz, 1H); 4.57-4.75 (m, 2H); 2.09 (m, 1H); 1.48-1.55 (m, 2H).

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Preparation BK: tert-butyl 3-hydroxy-3-(4-iodophenyl)azetidine-l-carboxylate:

Starting from teri-butyl 3-oxoazetidine-l-carboxylate (1 g; 5.84 mmol; commercial) and proceeding in analogy to Preparation BD, step BD.i, the title compound was obtained, after purification by CC (Hept-EA), as a white solid (1.29 g; 69% yield).

Ή NMR (ί/6-DMSO) 5: 7.74 (d, J = 8.5 Hz, 2H); 7.31 (d, J = 8.5 Hz, 2H); 6.42 (s, 1H);

3.94-4.08 (m, 4H); 1.41 (s, 9H).

Preparation BL: 3-(4-iodophenyl)azetidin-3-ol trifluoroacetate:

To a solution of the compound of Preparation BK (0.1 g, 0.26 mmol) in DCM (5 mL) at 0°C was added TFA (1.2 mL). After stirring at rt for 15 min., the mixture was concentrated 10 to dryness and the residue was triturated in a DCM-Et2O mixture. After drying, the title compound was obtained as a white solid (0.108 g; quant.).

’H NMR (ί/6-DMSO) 5: 7.81 (d, J = 8.5 Hz, 2H); 7.37 (d, J = 8.5 Hz, 2H); 6.76 (br. s, 1H); 4.31 (d, J = 11.4 Hz, 2H); 4.06 (d, J = 11.4 Hz, 2H).

MS (ESI, m/z): 275.88 [M+H⁺] for C9H10NOI; t_R = 0.48 min.

Preparation BM: 4-(4-iodophenyl)piperidin-4-ol:

Starting from terZ-butyl 3-oxopiperidine-1-carboxylate (0.226 g; 11 mmol; commercial) and proceeding in analogy to Preparation BD, step BD.i (77% yield) and Preparation BL (54% yield), the title compound was obtained, after basic work-up and purification by CC (DCM-MeOH containing 1% aq. NH4OH), as a yellowish solid (0.127 g).

’H NMR (ί/6-DMSO) 5: 7.74 (d, J = 8.5 Hz, 2H); 7.31 (d, J = 8.5 Hz, 2H); 6.42 (s, 1H);

3.94-4.08 (m, 4H); 1.41 (s, 9H).

MS (ESI, m/z): 375.8 [M+H⁺] for Ci₄Hi₈NO₃I; t_R = 0.87 min.

Preparation BN: V-(3-bromoprop-2-yn-l-yl)methanesulfonamide:

Starting from /V-(prop-2-yn-l-yl)methanesulfonamide (1.52 g; 11.4 mmol) and proceeding 25 in analogy to Preparation G, step G.iv (71% yield), the title compound was obtained after purification by CC (DCM-TBME), as a yellowish solid (1.71 g).

’H NMR (ί/6-DMSO) : 7.58 (t, J = 6.0 Hz, 1H); 3.87 (d, J = 6.1 Hz, 2H); 2.95 (s, 3H).

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REFERENCE EXAMPLES:

Reference Example 1: (R5)-A-hydroxy-4-(6-(4-(3-hydroxyoxetan-3-yl)phenyl)-3-oxoIH-pyrrolo [1,2-c] imidazol-2(3ZZ)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

REl.i. (RS)-4-(6-(4-(3-hydroxyoxetan-3-yl)phenyl)-3-oxo-lH-pyrrolo[l,2-c]imidazol5 2(3H)-yl)-2-methyl-2-(methylsulfonyl)-N-(((RS)-tetrahydro-2H-pyran-

2- yl)oxy)butanamide:

Starting from the compound of Preparation D (0.06 g; 0.119 mmol) and

3- (4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol (0.05 g;

0.179 mmol), and proceeding in analogy to Procedure A, the title compound, slightly contaminated with OPPI13, was obtained as a colourless oil (0.037 g; 57% yield).

MS (ESI, m/z): 548.07 [M+H⁺] for C26H33N3O8S; t_R = 0.70 min.

REl.ii. (RS)-N-hydroxy-4-(6-(4-(3-hydroxyoxetan-3-yl)phenyl)-3-oxolH-pyrrolo[l,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from intermediate REl.i (0.037 g; 0.02 mmol) and using Procedure D, the title 15 compound was obtained as a yellowish foam (0.008 g; 25% yield).

'HNMR (Λ-DMSO) 5: 7.63-7.73 (m, 2H); 7.51-7.63 (m, 3H); 6.55 (s, 1H); 6.28 (s, 1H); 4.76 (d, J = 6.45 Hz, 2H); 4.69 (d, J = 6.45 Hz, 2H); 4.48 (s, 2H); 3.45-3.58 (m, 1H);

3.34-3.44 (m, 1H); 3.07 (s, 3H); 2.56-2.66 (m, 1H); 1.93-2.04 (m, 1H); 1.54 (s, 3H).

MS (ESI, m/z): 464.0 [M+H⁺] for C21H25N3O7S; t_R = 0.80 min.

Reference Example 2: (RS)-4-(6-((4-(2-ethoxypropan-2-yl)phenyl)ethynyl)-3-oxo- //-pyrrolo[ 1,2-c] imidazol-2(3 //)-yl)-V-hydroxy-2-methyl-

2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation G (0.13 g; 0.31 mmol) and

2-(4-iodophenyl)propan-2-ol (0.121 g; 0.46 mmol; prepared as described in 25 JP 2008001635 A) and proceeding successively in analogy to Procedure E (51% yield) and

Procedure D (42% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a white solid (0.033 g).

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Ή NMR (ί/s-DMSO) δ: 10.83-11.07 (br. s, 1H); 9.03-9.33 (br. s, 1H); 7.30-7.57 (m, 5H);

6.24-6.29 (m, 1H); 4.46 (s, 2H); 3.33-3.56 (m, 2H); 3.15 (q, J = 6.9 Hz, 2H); 3.07 (s, 3H); 2.55-2.65 (m, 1H); 1.90-2.04 (m, 1H); 1.54 (s, 3H); 1.44 (s, 6H); 1.08 (t, J = 6.9 Hz, 3H). MS (ESI, m/z): 501.90 [M+H⁺] for C25H31N3O6S; t_R = 0.79 min.

Reference Example 3: (R5)-4-(6-((2-fluoro-4-(hydroxymethyl)phenyl)ethynyl)-3-oxolZf-pyrrolo [1,2-c] im idazol-2(3H)-y l)-V-hy droxy-2-methyl2-(methylsulfonyl)butanamide:

Starting from (4-ethynylphenyl)-2-fluoro-methanol (0.054 g; 0.36 mmol; prepared according to WO 2011/021209) and the compound of Preparation F (0.16 g; 0.3 mmol) and 10 proceeding successively in analogy to Procedure F (80% yield) and Procedure B (60% yield), the title compound was obtained, after precipitation in water and trituration in DCM, as a white solid (0.066 g).

Ή NMR (WDM SO) 5: 10.89-10.98 (br. s, 1H); 9.12-9.21 (br. s, 1H); 7.45-7.57 (m, 2H); 7.14-7.27 (m, 2H); 6.27-6.31 (m, 1H); 5.38 (t, J = 5.8 Hz, 1H); 4.53 (d, J = 5.8 Hz, 2H);

4.46 (s, 2H); 3.35-3.58 (m, 2H); 3.07 (s, 3H); 2.54-2.69 (m, 1H); 1.91-2.06 (m, 1H);

1.54 (s, 3H).

MS (ESI, m/z): 463.97 [M+H⁺] for C21H22N3O6FS; t_R = 0.68 min.

Reference Example 4: (R5)-/V-hydroxy-4-(6-(4-(3-hydroxy-3-methylbut-l-yn- l-yl)phenyl)-3-oxo-lZ/-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)-2-methyl-

2-(methylsulfonyl)butanamide:

RE4. i. (RS)-4-(6-(4-(3-hydroxy-3-methylbut-l-yn-l-yl)phenyl)-3-oxolH-pyrrolo[1,2-c] imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)-N-(((RS)-tetrahydro2H-pyran-2-yl)oxy)butanamide:

A mixture of Pd2(dba)3 (0.055 g; 0.06 mmol) and PCy3 (0.04 g; 0.144 mmol) in degassed 25 dioxane (4 mL) was premixed at 90°C for 5 min. To the mixture were added the compound of Preparation F (0.315 g; 0.6 mmol), the compound of Preparation I (0.122 g; 0.6 mmol) and a degassed IT/ K3PO4 solution (0.9 mL). The mixture was degassed and heated at 90°C for 1.5 h. After cooling, the reaction was concentrated to dryness and the residue was purified by CC (DCM-EA) to afford the title compound as a yellow oil (0.039 g;

12% yield).

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MS (ESI, m/z): 557.9 [M+H⁺] for C28H35N3O7S; t_R = 0.81 min

RE4.ii. (RS)-N-hydroxy-4-(6-(4-(3-hydroxy-3-methylbut-l-yn-l-yl)phenyl)-3-oxolH-pyrrolo[l,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from intermediate RE4.i (0.038 g; 0.068 mmol) and proceeding in analogy to

Procedure B, the title compound was obtained, after purification by CC (DCM-MeOH), as a white solid (0.005 g; 15% yield).

Ή NMR (Λ-DMSO) 5: 10.84-11.05 (br. s, IH); 9.07-9.27 (br. s, IH); 7.59-7.69 (m, 3H);

7.34 (d, J = 7.9 Hz, 2H); 6.52-6.59 (m, IH); 5.41-5.45 (br. s, IH); 4.48 (s, 2H);

3.35-3.58 (m, 2H); 3.07 (s, 3H); 2.55-2.68 (m, IH); 1.91-2.07 (m, IH); 1.54 (s, 3H);

1.47 (s,6H).

MS (ESI, m/z) : 473.96 [M+H⁺] for C23H27N3O6S; t_R = 0.70 min.

Reference Example 5: (R5)-/V-hydroxy-4-(6-(5-hydroxy-5-methylhexa-l,3-diyn-l-yl)-

3- oxo-l//-pyrrolo[ l,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation G (0.2 g; 0.472 mmol) and 4-iodo-2-methylbut15 3-yn-2-ol (0.119 g; 0.567 mmol; prepared as described in Rajender Reddy et al.,

Tetrahedron Lett. (2010), 51, 2170-2173), and proceeding successively in analogy to Procedure E (100% yield) and Procedure B (21% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a beige solid (0.041 g).

Ή NMR (Λ-DMSO) 5: 10.87-10.98 (br. s, IH); 9.17 (br. s, IH); 7.57 (s, IH); 6.26 (s, IH);

5.60 (s, IH); 4.42 (s, 2H); 3.44-3.52 (m, IH); 3.34-3.42 (m, IH); 3.06 (s, 3H);

2.54-2.65 (m, IH); 1.91-1.99 (m, IH); 1.52 (s, 3H); 1.41 (s, 6H).

MS (ESI, m/z): 421.93 [M+H⁺] for C19H23N3O6S; t_R = 0.66 min.

Reference Example 6: (R5)-/V-hydroxy-2-methyl-4-(6-((4-((4-methylpiperazin- l-yl)methyl)phenyl)ethynyl)-3-oxo-lZ/-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)-

2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation G (0.2 g; 0.472 mmol) and l-(4-iodobenzyl)-

4- methylpiperazine (0.179 g; 0.567 mmol; prepared as described in Chai et al., Chemistry - A European Journal (2011), 17, 10820-10824), and proceeding successively in

- 121 2015226250 05 Nov 2018 analogy to Procedure E (84% yield) and Procedure B (44% yield), the title compound was obtained as a yellow solid (0.093 g).

Ή NMR (rL-DMSO) 5: 10.75-11.10 (br. s, IH); 9.06-9.35 (br. s, IH); 7.45 (d, J = 8.1 Hz, 2H); 7.42 (s, IH); 7.31 (d, J = 8.1 Hz, 2H); 6.26 (s, IH); 4.46 (s, 2H);

3.47-3.53 (overlapped m, IH); 3.46 (overlapped s, 2H); 3.34-3.42 (overlapped m, IH);

3.06 (s, 3H); 2.50-2.62 (m, IH); 2.24-2.43 (m, 8H); 2.14 (s, 3H); 1.93-2.01 (m, IH);

1.53 (s, 3H).

MS (ESI, m/z): 527.97 [M+H⁺] for C26H33N5O5S; t_R = 0.52 min.

Reference Example 7: (RS)-/V-hydroxy-4-(6-(4-(2-hydroxyethoxy)phenyl)-3-oxo10 IZZ-pyrrolo [1,2-c] imidazol-2(3ZZ)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation D (0.3 g; 0.636 mmol) and (RS)-4,4,5,5-tetramethyl-2-(4-(2-((tetrahydro-2/7-pyran-2-yl)oxy)ethoxy)phenyl)-

1,3,2-dioxaborolane (0.233 g; 0.668 mmol; prepared according to EP 2418203 Al), and proceeding successively in analogy to Procedure A (19% yield) and Procedure B (46% 15 yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a white solid (0.0247 g).

Ή NMR (rL-DMSO) 5: 10.77-11.05 (br. s, IH); 9.05-9.22 (br. s, IH); 7.55 (d, J = 8.7 Hz, 2H); 7.48 (s, IH); 6.91 (d, J = 8.7 Hz, 2H); 6.47 (s, IH); 4.86 (t, J = 5.2 Hz, IH); 4.46 (s, 2H); 3.98 (t, J = 5.2 Hz, 2H); 3.71 (q, J = 5.2 Hz, 2H); 3.46-3.54 (m, IH);

3.30-3.40 (overlapped m, IH); 3.07 (s, 3H); 2.50-2.60 (overlapped m, IH); 1.93-2.00 (m,

IH); 1.53 (s, 3H).

MS (ESI, m/z): 451.92 [M+H⁺] for C20H25N3O7S; t_R = 0.60 min.

Reference Example 8: (RS)-/V-hydroxy-4-(6-(4-(2-methoxyethoxy)phenyl)-3-oxoΙΖΖ-pyrrolo [1,2-c] imidazol-2(3ZZ)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation D (0.2 g; 0.418 mmol) and

2-(4-(2-methoxyethoxy)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (0.14 g;

0.502 mmol; prepared according to US 2007/287708 Al), and proceeding successively in analogy to Procedure A (38% yield) and Procedure B (27% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a white solid (0.019 g).

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Ή NMR (ί/6-DMSO) δ: 10.90-11.06 (br. s, IH); 9.14-9.29 (br. s, IH); 7.56 (d, J = 8.6 Hz, 2H); 7.49 (s, IH); 6.92 (d, J = 8.7 Hz, 2H); 6.48 (s, IH); 4.47 (s, 2H); 4.08-4.12 (m, 2H); 3.63-3.69 (m, 2H); 3.47-3.56 (m, IH); 3.36-3.43 (m, IH); 3.32 (s, 3H); 3.08 (s, 3H);

2.56-2.66 (m, IH); 1.94-2.03 (m, IH); 1.54 (s, 3H).

MS (ESI, m/z): 465.85 [M+H⁺] for C21H27N3O7S; t_R = 0.69 min.

Reference Example 9: (R5)-4-(6-(2-fluoro-4-methylphenyl)-3-oxo1//-pyrrolo[ 1,2-c] imidazol-2(3//)-yl)-V-hydroxy-2-methyl-

2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation D (0.2 g; 0.418 mmol) and (2-fluoro10 4-methylphenyl)boronic acid (0.064 g; 0.42 mmol;commercial), and proceeding successively in analogy to Procedure A (51% yield) and Procedure B (32% yield), the title compound was obtained, after purification by CC (Hept-EA), as a white solid (0.027 g).

Ή NMR (ί/6-DMSO) 5: 10.95 (s, IH); 9.19 (s, IH); 7.61 (t, J = 8.2 Hz, IH); 7.42 (s, IH); 7.07 (d, J =12.6 Hz, IH); 7.03 (dd, J = 0.7, 7.9 Hz, IH); 6.54 (s, IH); 4.48 (s, 2H);

3.48-3.55 (m, IH); 3.36-3.43 (m, IH); 3.07 (s, 3H); 2.58-2.65 (m, IH); 2.31 (s, 3H);

1.95-2.02 (m, IH); 1.54 (s, 3H).

MS (ESI, m/z): 423.95 [M+H⁺] for C19H22N3O5FS; t_R = 0.75 min.

Reference Example 10: (R5)-4-(6-(3-fluoro-4-isopropoxyphenyl)-3-oxo1//-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-V-hydroxy-2-methyl20 2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation D (0.2 g; 0.418 mmol) and (3-fluoro4-isopropoxyphenyl)boronic acid (0.084 g; 0.42 mmol; commercial), and proceeding successively in analogy to Procedure A (29% yield) and Procedure B (43% yield), the title compound was obtained, after purification by CC (Hept-EA), as a white solid (0.025 g).

Ή NMR (ί/6-DMSO) δ: 10.95 (s, 1 H); 9.19 (s, 1 H); 7.59 (s, IH); 7.51 (d, J = 12.9 Hz, IH); 7.38 (d, J = 8.5 Hz, IH); 7.13 (m, IH); 6.51 (s, IH); 4.57-4.63 (m, IH); 4.46 (s, 2H);

3.46-3.53 (m, IH); 3.34-3.41 (m, IH); 3.07 (s, 3H); 1.94-2.01 (m, IH); 1.53 (s, 3H); 1.28 (m, 6H).

MS (ESI, m/z): 467.98 [M+H⁺] for C21H26N3O6FS; t_R = 0.78 min.

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EXAMPLES OF COMPOUNDS ACCORDING TO THE INVENTION:

Example 1: (/?)-4-(6-(2-fluoro-4-methoxyphenyl)-3-oxo-lZ/-pyrrolo[l,2-c]imidazol2(3Z/)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide:

l.i. (R)-4-(6-(2-fluoro-4-methoxyphenyl)-3-oxo-lH-pyrrolo[l,2-c]imidazol-2(3H)-yl)-

2-methyl-2-(methylsulfonyl)-N-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide:

Starting from the compound of Preparation C (0.78 g; 1.63 mmol) and 2-fluoro-

4-methoxyphenylboronic acid (0.3 g; 1.8 mmol) and proceeding in analogy to Procedure A, the title compound as a yellowish foam (0.4 g, 48% yield).

Ή NMR (i/s-DMSO) (mixture of stereoisomers) δ: 11.39 (overlapped br. s, 0.5H);

11.34 (overlapped br. s, 0.5H); 7.62 (t, J = 8.4 Hz, IH); 7.36 (d, J = 6.7 Hz, IH); 6.88 (dd,

J = 2.4, 13.3 Hz, IH); 6.81 (dd, J = 2.4, 8.4 Hz, IH); 6.50 (s, IH); 4.85-4.88 (m, 0.5H);

4.39-4.52 (m, 2.5H); 3.99-4.05 (m, 0.5H); 3.88-3.97 (m, 0.5H); 3.78 (s, 3H); 3.36-3.58 (m, 3H); 3.07 (s, 1.5H); 3.04 (s, 1.5H); 2.54-2.71 (m, IH); 1.92-2.03 (m, IH); 1.60-1.68 (m, 2H); 1.58 (s, 1.5H); 1.56 (s, 1.5H); 1.33-1.54 (m, 4H).

MS (ESI, m/z): 523.97 [M+H⁺] for C24H30N3O7FS; t_R = 0.85 min.

l.ii. (R)-4-(6-(2-fluoro-4-methoxyphenyl)-3-oxo-lH-pyrrolo[l,2-c]imidazol-2(3H)-yl)-

N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide:

Starting from intermediate l.i (0.44 g; 0.84 mmol) and using Procedure B, the title compound was obtained, after purification by CC (DCM-MeOH), as a white solid (0.23 g;

63% yield).

Ή NMR (ί/s-DMSO) 5: 10.81-11.05 (br. s, IH); 9.14-9.23 (br. s, IH); 7.63 (t, J = 8.8 Hz, IH); 7.36-7.39 (m, IH); 6.88 (dd, J = 2.4, 13.3 Hz, IH); 6.81 (dd, J = 2.4, 8.5 Hz, IH); 6.49-6.51 (m, IH); 4.48 (s, 2H); 3.78 (s, 3H); 3.47-3.54 (m, IH); 3.35-3.42 (m, IH); 3.07 (s, 3H); 2.57-2.62 (m, IH); 1.94-2.02 (m, IH); 1.54 (s, 3H).

MS (ESI, m/z): 439.93 [M+H⁺] for C19H22N3O6FS; t_R = 0.73 min.

- 1242015226250 05 Nov 2018

Example 2: (/?)- V-hydroxy-4-(6-((4-(3-hydroxyoxetan-3-yl)phenyl)ethynyl)-3-oxolZ7-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

2.1. (RS)-N-hydroxy-4-(6-((4-(3-hydroxyoxetan-3-yl)phenyl)ethynyl)-3-oxolH-pyrrolo[l,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation G (0.13 g; 0.31 mmol) and the compound of Preparation J (0.127 g; 0.46 mmol) and proceeding successively in analogy to Procedure E and Procedure D, the title compound was obtained, after purification by prep-HPLC (Method 1), as a yellow solid (0.038 g; 45% yield).

MS (ESI, m/z): 488.00 [M+H⁺] for C23H25N3O7S; t_R = 0.64 min.

2.ii. (R)-N-hydroxy-4-(6-((4-(3-hydroxyoxetan-3-yl)phenyl)ethynyl)-3-oxolH-pyrrolo[l,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Intermediate 2.i (0.032 g) was separated by semi-preparative chiral HPLC Method D (Hept-EtOH-TFA 3-7-0.01; flow rate: 16 mL/min; UV detection at 210 nm); the respective retention times (flow rate: 0.8 mL/min) were 8.14 and 11.41 min. The title (R)-enantiomer, 15 identified as the second eluting compound, was obtained as a yellow solid (0.007 g).

Ή NMR (iA-DMSO) 5: 10.90-10.96 (br. s, 1H); 9.14-9.20 (br. s, 1H); 7.63 (d, J = 8.3 Hz, 2H); 7.52 (d, J = 8.3 Hz, 2H); 7.46 (s, 1H); 6.42 (s, 1H); 6.28 (s, 1H); 4.77 (d, J = 6.5 Hz, 2H); 4.67 (d, J = 6.5 Hz, 2H); 4.46 (s, 2H); 3.37-3.56 (m, 2H); 3.07 (s, 3H); 2.58-2.65 (m, 1H); 1.89-2.04 (m, 1H); 1.54 (s, 3H).

MS (ESI, m/z): 488.00 [M+H⁺] for C23H25N3O7S; t_R = 0.64 min.

Example 3: (R)-N-hydroxy-4-(6-((4-(hydroxymethyl)phenyl)ethynyl)-3-oxolZF-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

3.1. (RS)-N-hydroxy-4-(6-((4-(hydroxymethyl)phenyl)ethynyl)-3-oxolH-pyrrolo[l,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation F (0.2 g; 0.381 mmol) and 4-ethynylbenzyl alcohol (0.06 g; 0.457 mmol), and proceeding successively in analogy to Procedure E (48% yield) and Procedure F (69% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a beige solid (0.056 g).

MS (ESI, m/z): 445.98 [M+H⁺] for C21H23N3O6S; t_R = 0.65 min.

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3. ii. (R)-N-hydroxy-4-(6-((4-(hydroxymethyl)phenyl)ethynyl)-3-oxolH-pyrrolo[l,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Intermediate 3,i (0.05 g) was separated by semi-preparative chiral HPLC Method D (Hept-EtOH-TEA: 1-9-0.01; flow rate: 16 mL/min; UV detection at 287 nm); the respective retention times (flow rate: 0.8 mL/min) were 6.34 and 8.48 min. The title (R)-enantiomer, identified as the second eluting compound, was obtained as a yellow solid (0.01 g).

Ή NMR (i/₆-DMSO) 5: 10.73-11.11 (br. s, IH); 9.05-9.34 (br. s, IH); 7.41-7.47 (m, 3H);

7.34 (d, J = 8.2 Hz, 2H); 6.25-6.28 (m, IH); 5.25 (t, J = 5.8 Hz, IH); 4.51 (d, J = 5.7 Hz, 10 2H); 4.43-4.48 (m, 2H); 3.37-3.56 (m, 2H); 3.06 (s, 3H); 2.55-2.66 (m, IH); 1.90-2.04 (m,

IH); 1.53 (s, 3H).

MS (ESI, m/z): 445.98 [M+H⁺] for C21H23N3O6S; t_R = 0.65 min.

Example 4: (/?)-/V-hydroxy-4-(6-((3-hydroxyoxetan-3-yl)buta-l,3-diyn-l-yl)-3-oxolZf-pyrrolo [1,2-c] imidazol-2(3Z/)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.285 g; 0.586 mmol) and the compound of Preparation K (0.143 g; 0.64 mmol), and proceeding successively in analogy to Procedure G (51% yield) and Procedure B (37% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a beige solid (0.048 g).

'HNMR^-DMSO) 5: 10.87-11.00 (br. s, IH); 9.12-9.21 (br. s, IH); 7.61-7.64 (m, IH); 20 6.69-6.72 (m, IH); 6.28-6.31 (m, IH); 4.69 (d, J = 6.4 Hz, 2H); 4.54 (d, J = 6.4 Hz, 2H);

4.42-4.46 (m, 2H); 3.33-3.54 (m, IH); 3.06 (s, 3H); 2.50-2.75 (overlapped m, IH);

2.32-2.50 (overlapped m, IH); 1.87-2.04 (m, IH); 1.52 (s, 3H).

MS (ESI, m/z): 435.86 [M+H⁺] for C19H21N3O7S; t_R = 0.60 min.

Example 5: (/?)-/V-hydroxy25 4-(6-((4-((l/?,2/?)-2-(hydroxymethyl)cyclopropyl)phenyl)ethynyl)-3-oxolZf-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.097 g; 0.229 mmol) and the first-eluting enantiomer of Preparation L (0.07 g; 0.255 mmol), and proceeding successively in analogy to Procedure E (93% yield) and Procedure B (22% yield), the title compound was obtained, 30 after purification by prep-HPLC (Method 1), as a beige solid (0.023 g).

- 126 2015226250 05 Nov 2018

Ή NMR (ί/s-DMSO) δ: 10.77-11.06 (br. s, 1H); 9.08-9.28 (br. s, 1H); 7.43 (s, 1H);

7.35 (d, J = 7.9 Hz, 2H); 7.08 (d, J = 7.9 Hz, 2H); 6.25 (s, 1H); 4.63 (t, J = 5.6 Hz, 1H);

4.45 (s, 2H); 3.42-3.53 (m, 2H); 3.30-3.42 (overlapped m, 2H); 3.07 (s, 3H); 2.54-2.65 (m,

1H); 1.93-2.01 (m, 1H); 1.77-1.83 (m, 1H); 1.53 (s, 3H); 1.24-1.35 (m, 1H); 0.83-0.93 (m, 5 2H).

MS (ESI, m/z): 485.92 [M+H⁺] for C24H27N3O6S; t_R = 0.71 min.

Example 6: (/?)-V-hydroxy-

4-(6-((4-((15,25)-2-(hydroxymethyl)cyclopropyl)phenyl)ethynyl)-3-oxo- lH-pyrrolo [1,2-c] imidazol-2(3ZZ)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.118 g; 0.279 mmol) and the second-eluting enantiomer of Preparation L (0.083 g; 0.301 mmol), and proceeding successively in analogy to Procedure E (99% yield) and Procedure B (21% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a beige solid (0.027 g).

Ή NMR (ok-DMSO) 5: 10.60-11.21 (br. s, 1H); 9.00-9.36 (br. s, 1H); 7.43 (s, 1H); 7.34 (d, J = 7.9 Hz, 2H); 7.08 (d, J = 7.9 Hz, 2H); 6.25 (s, 1H); 4.60-4.67 (m, 1H); 4.45 (s, 2H); 3.42-3.53 (m, 2H); 3.30-3.42 (overlapped m, 2H); 3.06 (s, 3H);

2.50-2.63 (overlapped m, 1H); 1.92-2.01 (m, 1H); 1.77-1.84 (m, 1H); 1.52 (s, 3H);

1.24-1.35 (m, 1H); 0.83-0.93 (m, 2H).

MS (ESI, m/z): 485.91 [M+H⁺] for C24H27N3O6S; t_R = 0.71 min.

Example 7: (/?)-/V-hydroxy-4-(6-((4-(l-(hydroxymethyl)cyclopropyl)phenyl)ethynyl)-

3-oxo-lZZ-pyrrolo[l,2-c]imidazol-2(3ZZ)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation E (0.15 g; 0.286 mmol) and the compound of Preparation M (0.054 g; 0.314 mmol), and proceeding successively in analogy to 25 Procedure F (55% yield) and Procedure B (63% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a white solid (0.049 g).

Ή NMR (i/₆-DMSO) 5: 10.86-11.07 (br. s, 1H); 9.05-9.23 (br. s, 1H); 7.44 (s, 1H);

7.38 (d, J = 8.2 Hz, 2H); 7.30 (d, J = 8.2 Hz, 2H); 6.25 (s, 1H); 4.71 (t, J = 5.6 Hz, 1H);

4.45 (s, 2H); 3.54 (d, J = 5.6 Hz, 2H); 3.45-3.52 (overlapped m, 1H); 3.34-3.42 (m, 1H);

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2015226250 05 Nov 2018

3.07 (s, 3H); 2.55-2.62 (m, 1H); 1.93-2.00 (m, 1H); 1.52 (s, 3H); 0.85-0.88 (m, 2H); 0.74-0.78 (m, 2H).

MS (ESI, m/z): 485.94 [M+H⁺] for C24H27N3O6S; t_R = 0.72 min.

Example 8: (R)-4-(6-((4-(l-(ammomethyl)cyclopropyl)phenyl)ethynyl)-3-oxo5 IZZ-pyrrolo [1,2-c] im idazol-2(3H)-y l)-V-hy droxy-2-methyl2-(methylsulfonyl)butanamide formate:

Starting from the compound of Preparation E (0.15 g; 0.286 mmol) and the compound of Preparation N (0.1 g; 0.58 mmol), and proceeding successively in analogy to Procedure F (45% yield) and Procedure B (36% yield), the title compound was obtained, after 10 purification by prep-HPLC (Method 1), as a white solid (0.023 g).

Ή NMR (i/₆-DMSO) 5: 8.73-9.53 (br. s, 1H); 7.41-7.47 (m, 3H); 7.35 (d, J = 8.0 Hz, 2H);

6.25 (s, 1H); 4.45 (s, 2H); 3.45-3.54 (m, 1H); 3.30-3.43 (overlapped m, 1H); 3.07 (s, 3H);

2.95 (s, 2H); 2.50-2.62 (overlapped m, 1H); 1.93-2.01 (m, 1H); 1.53 (s, 3H); 0.93-0.97 (m, 2H); 0.83-0.87 (m, 2H).

MS (ESI, m/z): 485.00 [M+H⁺] for C24H28N4O5S; t_R = 0.59 min.

Example 9: (R)-/V-hydroxy-4-(6-((4-(l-hydroxy-2-methylpropan2-yl)phenyl)ethynyl)-3-oxo-lZZ-pyrrolo[l,2-c]imidazol-2(3ZZ)-yl)-2-methyl2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation E (0.15 g; 0.286 mmol) and the compound of 20 Preparation O (0.055 g; 0.31 mmol), and proceeding successively in analogy to

Procedure F (99% yield) and Procedure B (27% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a white solid (0.037 g).

Ή NMR (i/s-DMSO) 5: 10.85-11.03 (br. s, 1H); 9.11-9.23 (br. s, 1H); 7.44 (s, 1H);

7.36-7.42 (m, 4H); 6.26 (s, 1H); 4.70 (t, J = 5.3 Hz, 1H); 4.45 (s, 2H); 3.46-3.53 (m, 1H);

3.41 (d, J = 5.3 Hz, 2H); 3.30-3.41 (overlapped m, 1H); 3.07 (s, 3H);

2.57-2.61 (overlapped m, 1H); 1.93-2.00 (m, 1H); 1.53 (s, 3H); 1.22 (s, 6H).

MS (ESI, m/z): 487.98 [M+H⁺] for C24H29N3O6S; t_R = 0.74 min.

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Example 10: (/?)-/V-hydroxy-4-(6-((4-(2-hydroxypropan-2-yl)phenyl)ethynyl)-3-oxolZf-pyrrolo [1,2-c] imidazol-2(3Z/)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.235 g; 0.556 mmol) and

2- (4-iodophenyl)propan-2-ol (0.16 g; 0.61 mmol, prepared as described in

JP 2008001635 Al), and proceeding successively in analogy to Procedure E (47% yield) and Procedure B (61% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a beige solid (0.076 g).

Ή NMR (i/₆-DMSO) 5: 10.88-11.05 (br. s, IH); 9.08-9.25 (br. s, IH); 7.46-7.50 (m, 2H);

7.45 (d, J = 1.2 Hz, IH); 7.40-7.43 (m, 2H); 6.26 (d, J = 1.2 Hz, IH); 5.09 (s, IH); 4.46 (s, 10 2H); 3.46-3.53 (m, IH); 3.35-3.43 (m, IH); 3.07 (s, 3H); 2.56-2.61 (m, IH); 1.93-2.00 (m,

IH); 1.52 (s, 3H); 1.42 (s, 6H).

MS (ESI, m/z): 473.99 [M+H⁺] for C23H27N3O6S; t_R = 0.70 min.

Example 11: (/?)-4-(6-((5)-5,6-dihydroxyhexa-l,3-diyn-l-yl)-3-oxolZf-pyrrolo [1,2-c] im idazol-2(3//)-y l)-V-hy droxy-2-methyl15 2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.128 g; 0.302 mmol) and (S)-4-iodobut-

3- yne-l,2-diol (0.09 g; 0.423 mmol; prepared as described in Wang et al., J. Org.

Chem. (2001), 66, 2146-2148), and proceeding successively in analogy to Procedure G (27% yield) and Procedure D (30% yield), the title compound was obtained, after 20 purification by prep-HPLC (Method 1), as a beige solid (0.01 g).

Ή NMR (i/₆-DMSO) 5: 8.66-9.87 (br. s, IH); 8.31 (s, IH); 7.59 (s, IH); 6.28 (d,

J= 1.2 Hz, IH); 5.55-5.81 (br.s, IH); 4.91-5.17 (br.s, IH); 4.43 (s, 2H); 4.31 (t, J = 6.1 Hz,

IH); 3.45-3.52 (overlapped m, IH); 3.44 (d, J = 6.1 Hz, 2H); 3.40-3.45 (overlapped m,

IH); 3.06 (s, 3H); 2.54-2.62 (overlapped m,lH); 1.93-1.99 (m, IH); 1.52 (s, 3H).

MS (ESI, m/z): 423.90 [M+H⁺] for C18H21N3O7S; t_R = 0.53 min.

- 129 2015226250 05 Nov 2018

Example 12: (/?)-V-hyd roxv-4-(6-(5-(( /.S',2.$')-2-(hvdroxymethyl)cyclopropyl)penta- l,3-diyn-l-yl)-3-oxo-lZZ-pyrrolo[l,2-c]imidazol-2(3ZZ)-yl)-2-methyl-

2- (methylsulfonyl)butanamide:

12. i. ((lS,2S)-2-((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-3-oxo-

2,3-dihydro-lH-pyrrolo[l,2-c]imidazol-6-yl)buta-l, 3-diyn-l-yl)cyclopropyl)methyl acetate:

CuCl (0.01 g; 0.1 mmol) was added to a solution of nBuNH₂ (30% in water; 0.3 g in 0.7 mL) at rt. NH₂OH.HC1 (0.099 g; 1.42 mmol) was added. The compound of Preparation H (0.4 g; 0.95 mmol) was added and the solution was immediately ice-chilled.

The (/.S’,2.S’)-conf'igurated compound of Preparation? (0.308 g; 1.42 mmol) in Et₂O (0.5 mL) was added in one portion. The reaction proceeded at rt overnight. The reaction mixture was diluted with water (40 mL) and extracted with EA (4 x 60 mL). The combined org. layers were dried over MgSCL, filtered and evaporated under reduced pressure. The residue was purified by CC (DCM-MeOH) to afford the title compound as a yellow foam (0.252 g; 56% yield).

Ή NMR (flk-DMSO) 5: 10.89-10.98 (br. s, 1H); 9.14-9.21 (br. s, 1H); 7.53 (s, 1H); 6.23-6.24 (m, 1H); 4.42 (s, 2H); 3.93-3.99 (m, 1H); 3.78-3.85 (m, 1H); 3.44-3.52 (m, 1H);

3.34-3.42 (m, 1H); 3.05 (s, 3H); 2.54-2.62 (m, 1H); 2.03 (s, 3H); 1.91-2.00 (m, 1H);

1.57-1.63 (m, 1H); 1.53-1.57 (m, 1H); 1.52 (s, 3H); 0.99-1.04 (m, 1H); 0.91-0.97 (m, 1H).

MS (ESI, m/z): 475.99 [M+H⁺] for C₂₂H₂₅N₃O₇S; t_R = 0.76 min.

12. ii. (R)-N-hydroxy-4-(6-(5-((lS,2S)-2-(hydroxymethyl)cyclopropyl)penta-l,3-diyn-l-yl)-

3- oxo-lH-pyrrolo[l,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

To a solution of intermediate 12.i (0.252 g; 0.53 mmol) in MeOH (3 mL) was added K₂CO₃ (0.146 g; 1.06 mmol). The reaction mixture was stirred at rt for 30 min. Water (1 mL) was added and the reaction mixture was directly purified by prep-HPLC (Method 1) to afford the title compound as a white solid (0.085 g; 37% yield).

Ή NMR (ί/s-DMSO) 5: 10.84-11.05 (br. s, 1H); 9.02-9.20 (br. s, 1H); 7.52 (s, 1H); 6.24 (d, J=l.lHz, 1H); 4.69 (t, J = 5.8Hz, 1H); 4.42 (s, 2H); 3.43-3.51 (m, 1H);

3.37-3.43 (m, 2H); 3.21-3.27 (m, 1H); 3.05 (s, 3H); 2.55-2.63 (m, 1H); 1.92-1.99 (m, 1H);

1.51 (s, 3H); 1.35-1.43 (m, 2H); 0.87-0.91 (overlapped m, 1H); 0.81-0.87 (overlapped m,

1H).

- 130 2015226250 05 Nov 2018

MS (ESI, m/z): 433.95 [M+H⁺] for C20H23N3O6S; t_R = 0.66 min.

Example 13: (/?)-/V-hydroxy-4-(6-((4-((/?)-l-hydroxyethyl)phenyl)ethynyl)-3-oxolZf-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.203 g; 0.479 mmol) and 5 (R)-l-(4-iodophenyl)ethan-l-ol (0.131 g. 0.527 mmol; commercial), and proceeding successively in analogy to Procedure E (50% yield) and Procedure B (65% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a beige solid (0.06 g).

Ή NMR (flk-DMSO) δ: 10.72-11.03 (br. s, 1H); 9.07-9.23 (br. s, 1H); 7.44 (d, J = 5.4 Hz, 10 2H); 7.42 (s, 1H); 7.36 (d, J = 5.4 Hz, 2H); 6.27 (s, 1H); 5.23 (d, J = 4.1 Hz, 1H); 4.73 (q,

J = 6.4 Hz, 1H); 4.45 (s, 2H); 3.46-3.54 (m, 1H); 3.30-3.36 (overlapped m, 1H); 3.07 (s, 3H); 2.50-2.62 (overlapped m, 1H); 1.93-2.00 (m, 1H); 1.53 (s, 3H); 1.31 (d, J = 6.4 Hz, 3H).

MS (ESI, m/z): 459.97 [M+H⁺] for C22H25N3O6S; t_R = 0.68 min.

Example 14: (7?)-/V-hydroxy-4-(6-((4-((5)-l-hydroxyethyl)phenyl)ethynyl)-3-oxolZZ-pyrrolo [1,2-c] imidazol-2(3ZZ)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.16 g; 0.378 mmol) and (S)-l-(4-iodophenyl)ethan-l-ol (0.103 g; 0.416 mmol; commercial), and proceeding successively in analogy to Procedure E (25% yield) and Procedure B (17% yield), the title 20 compound was obtained, after purification by prep-HPLC (Method 1), as a beige solid (0.006 g).

Ή NMR (rt6-DMSO) δ: 10.20-11.60 (br. s, 1H); 8.94-9.73 (br. s, 1H); 7.45 (s, 1H);

7.43 (d, J = 8.2 Hz, 2H); 7.36 (d, J = 8.2 Hz, 2H); 6.26 (d, J = 1.0 Hz, 1H); 5.22-5.57 (m, 1H); 4.70-4.76 (m, 1H); 4.46 (s, 2H); 3.46-3.54 (m, 1H); 3.30-3.43 (overlapped m, 1H);

3.07 (s, 3H); 2.57-2.65 (m, 1H); 1.93-2.01 (m, 1H); 1.53 (s, 3H); 1.31 (d, J = 6.5 Hz, 3H).

MS (ESI, m/z): 460.00 [M+H⁺] for C22H25N3O6S; t_R = 0.68 min.

- 131 2015226250 05 Nov 2018

Example 15: (/?)-N-hydroxy-4-(6-((l-(hydroxymethyl)cyclopropyl)buta-l,3-diyn-

1- yl)-3-oxo-lZ/-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)-2-methyl-

2- (methylsulfonyl)butanamide:

15. i. (2R)-4-(6-((l-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)buta-l,3-diyn-l-yl)5 3-oxo-lH-pyrrolo[l,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)N-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide:

Starting from the compound of Preparation H (0.2 g; 0.472 mmol) and the compound of Preparation Q (0.205 g; 0.495 mmol; commercial), and proceeding in analogy to Example 12, step 12.i, the title compound was obtained, after purification by CC 10 (Hept-EA), as a white foam (0.118 g; 33% yield).

'H NMR (i/i-DMSO) (mixture of stereoisomers) δ: 11.34-11.40 (br. s, 0.5H); 11.29-11.34 (br. s, 0.5H); 7.63-7.67 (m, 4H); 7.53-7.55 (m, 1H); 7.42-7.50 (m, 6H);

6.24-6.27 (m, 1H); 4.83-4.86 (m, 0.5H); 4.36-4.47 (m, 2.5H); 3.97-4.05 (m, 0.5H);

3.89-3.96 (m, 0.5H); 3.62 (s, 2H); 3.37-3.57 (m, 3H); 3.07 (s, 1.5H); 3.04 (s, 1.5H);

2.54-2.62 (m, 1H); 1.90-1.99 (m, 1H); 1.59-1.66 (m, 2H); 1.56 (s, 1.5H); 1.54 (s, 1.5H);

I. 42-1.52 (overlapped m, 4H); 1.03 (s, 9H); 0.94-0.99 (m, 2H); 0.83-0.88 (m, 2H).

MS (ESI, m/z): 382.99 [M+H⁺] for C₄iH₄9N3O₇SSi; t_R = 1.11 min.

15.ii. (2R)-4-(6-((l-(hydroxymethyl)cyclopropyl)buta-l,3-diyn-l-yl)-3-oxolH-pyrrolo[l,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)-N-(((RS)-tetrahydro-

2H-pyran-2-yl)oxy)butanamide:

To a solution of intermediate 15.i (0.066 g; 0.0873 mmol) in THF (2 mL) was added TBAF \M (0.175 mmol). The reaction was stirred at rt for 1 h. DCM (20 mL) and water (20 mL) were added. The aq. phase was extracted with EA (2 x 20 mL). The combined org. layers were dried over MgSO₄, filtered and concentrated to dryness. The residue was 25 purified by CC (Hept-EA) to afford the title compound as a colourless oil (0.035 g;

77% yield).

'H NMR (ίΑ-DMSO) (mixture of stereoisomers) δ: 11.34-11.39 (br. s; 0.5H);

II. 29-11.34 (br.s; 0.5H); 7.52 (s, 0.5H); 7.53 (s, 0.5H); 6.22-6.25 (m, 1H); 5.00 (t, J = 6.0 Hz, 1H); 4.84-4.87 (m, 0.5H); 4.36-4.49 (m, 2.5H); 3.98-4.07 (m, 0.5H);

3.90-3.97 (m, 0.5H); 3.46-3.56 (m, 1.5H); 3.38-3.45 (overlapped m, 1.5H); 3.37 (d,

J = 6.0 Hz, 2H); 3.06 (s, 1.5H); 3.03 (s, 1.5H); 2.53-2.64 (m, 1H); 1.93-2.02 (m, 1H);

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1.60-1.68 (m, 2H); 1.56 (s, 1.5H); 1.55 (s, 1.5H); 1.43-1.53 (overlapped m, 4H);

0.87-0.91 (m, 2H); 0.81-0.86 (m, 2H).

MS (ESI, m/z): 517.86 [M+H⁺] for C25H31N3O7S; t_R = 0.78 min.

15. iii. (R)-N-hydroxy-4-(6-((I-(hydroxymethyl)cyclopropyl)buta-l,3-diyn-l-yl)-3-oxo5 lH-pyrrolo[l,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from intermediate 15.ii (0.035 g; 0.066 mmol) and proceeding in analogy to Procedure D, the title compound was obtained, after precipitation in water, as a white solid (0.013 g, 46% yield).

Ή NMR (i/₆-DMSO) δ: 10.87-10.97 (br. s, 1H); 9.14-9.20 (br. s, 1H); 7.53 (s, 1H); 10 6.24 (d, J=l.lHz, 1H); 5.00 (t, J = 6.1Hz, 1H); 4.43 (s, 2H); 3.45-3.51 (m, 1H);

3.38 (overlapped d, J = 6.1 Hz, 2H); 3.36-3.41 (overlapped m, 1H); 3.06 (s, 3H);

2.54-2.63 (m, 1H); 1.92-2.00 (m, 1H); 1.52 (s, 3H); 0.88-0.91 (m, 2H); 0.83-0.87 (m, 2H). MS (ESI, m/z) : 433.98 [M+H⁺] for C20H23N3O6S; t_R = 0.66 min.

Example 16: (/?)-V-hydroxy-4-(6-((4-(2-hydroxyethyl)phenyl)ethynyl)-3-oxo15 lH-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.194 g; 0.457 mmol) and 2-(4-iodophenyl)ethanol (0.125 g; 0.503 mmol; commercial), and proceeding successively in analogy to Procedure E (49% yield) and Procedure B (61% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a beige solid (0.063 g).

Ή NMR (ί/s-DMSO) δ: 10.81-11.08 (br. s, 1H); 9.11-9.27 (br. s, 1H); 7.44 (s, 1H);

7.39 (d, J = 8.1 Hz, 2H); 7.24 (d, J = 8.1 Hz, 2H); 6.26 (s, 1H); 4.66 (t, J = 5.2 Hz, 1H);

4.45 (s, 2H); 3.58-3.63 (m, 2H); 3.46-3.53 (m, 1H); 3.36-3.43 (m, 1H); 3.07 (s, 3H);

2.73 (t, J = 6.9 Hz, 2H); 2.56-2.62 (m, 1H); 1.93-2.01 (m, 1H); 1.53 (s, 3H).

MS (ESI, m/z): 459.98 [M+H⁺] for C22H25N3O6S; t_R = 0.67 min.

Example 17: (/?)-4-(6-((4-((/?)-l,2-dihydroxyethyl)phenyl)ethynyl)-3-oxolZf-pyrrolo [1,2-c] im idazol-2(3//)-y l)-V-hy d roxy-2-methy 12-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.194 g; 0.457 mmol) and (R)-l-(4-iodophenyl)-l,2-ethanediol (0.133 g; 0.503 mmol; commercial), and proceeding

- 133 2015226250 05 Nov 2018 successively in analogy to Procedure E (72% yield) and Procedure B (52% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a light brown solid (0.081 g).

Ή NMR (flk-DMSO) δ: 10.84-11.04 (br. s, 1H); 9.14-9.23 (br. s, 1H); 7.45 (s, 1H); 5 7.42 (d, J = 8.2 Hz, 2H); 7.36 (d, J = 8.2 Hz, 2H); 6.27 (s, 1H); 5.32 (d, J = 4.3 Hz, 1H);

4.74 (t, J = 5.9 Hz, 1H); 4.52-4.58 (m, 1H); 4.46 (s, 2H); 3.46-3.53 (m, 1H); 3.35-3.46 (m, 3H); 3.07 (s, 3H); 2.56-2.62 (m, 1H); 1.94-2.01 (m, 1H); 1.53 (s, 3H).

MS (ESI, m/z): 475.99 [M+H⁺] for C22H25N3O7S; t_R = 0.58 min.

Example 18: (/?)-4-(6-((4-((5)-l,2-dihydroxyethyl)phenyl)ethynyl)-3-oxo10 IZZ-py rrolo [1,2-c] im idazol-2(3H)-y l)-V-hy droxy-2-methyl-

2- (methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.194 g; 0.457 mmol) and (S)-l-(4-iodophenyl)-l,2-ethanediol (0.133 g; 0.503 mmol; commercial), and proceeding successively in analogy to Procedure E (69% yield) and Procedure B (50% yield), the title 15 compound was obtained, after purification by prep-HPLC (Method 1), as a light brown solid (0.074 g).

Ή NMR (i/₆-DMSO) δ: 10.93 (br. s, 1H); 9.15-9.22 (br. s, 1H); 7.45 (s, 1H); 7.42 (d, J = 8.2 Hz, 2H); 7.36 (d, J = 8.2 Hz, 2H); 6.27 (s, 1H); 5.32 (d, J = 4.3 Hz, 1H); 4.74 (t, J = 5.9 Hz, 1H); 4.53-4.58 (m, 1H); 4.46 (s, 2H); 3.46-3.53 (m, 1H); 3.35-3.46 (m, 3H);

3.07 (s, 3H); 2.56-2.62 (m, 1H); 1.94-2.01 (m, 1H); 1.53 (s, 3H).

MS (ESI, m/z): 475.99 [M+H⁺] for C22H25N3O7S; t_R = 0.58 min.

Example 19: (/?)-4-(6-((2-fluoro-4-(l-(hydroxymethyl)cyclopropyl)phenyl)ethynyl)-

3- oxo-lZZ-pyrrolo[l,2-c]imidazol-2(3ZZ)-yl)-/V-hydroxy-2-methyl2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.183 g; 0.432 mmol) and the compound of Preparation R (0.139 g; 0.475 mmol), and proceeding successively in analogy to Procedure E (46% yield) and Procedure B (58% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a yellow solid (0.058 g).

Ή NMR (flk-DMSO) δ: 10.89-10.99 (br. s, 1H); 9.14-9.20 (br. s, 1H); 7.48 (s, 1H); 7.44 (t, 30 J = 8.1 Hz, 1H); 7.19 (dd, J = 1.7, 11.4 Hz, 1H); 7.12 (dd, J = 1.7, 11.4 Hz, 1H); 6.28 (s,

- 134 2015226250 05 Nov 2018

1H); 4.78 (t, J = 5.6 Hz, 1H); 4.46 (s, 2 H), 3.55 (d, J = 5.6 Hz, 2H); 3.45-3.53 (m, 1H);

3.36-3.43 (m,l H), 3.07 (s, 3H); 2.57-2.64 (m, 1H); 1.93-2.00 (m, 1H); 1.53 (s, 3H); 0.88-0.91 (m, 2H); 0.81-0.84 (m, 2H).

MS (ESI, m/z): 503.99 [M+H⁺] for C24H26N3O6FS; t_R = 0.73 min.

Example 20: (/?)-7V-hydroxy-4-(6-((4-(3-(2-hydroxyethyl)-2-oxoimidazolidm-

1- yl)phenyl)ethynyl)-3-oxo-lZ/-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)-2-methyl-

2- (methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.16 g; 0.378 mmol) and the compound of Preparations (0.138 g; 0.416 mmol), and proceeding successively in analogy to 10 Procedure E (59% yield) and Procedure B (58% yield), the title compound was obtained, after precipitation in water and EtOH and recrystallisation from DMF/MeCN (6/94), as a beige solid (0.070 g).

Ή NMR (%-DMSO) δ: 10.88-11.05 (br. s, 1H); 9.17-9.22 (br. s, 1H); 7.60 (d, J = 8.3 Hz, 2H); 7.40-7.45 (m, 3H); 6.25 (s, 1H); 4.75 (t, J = 5.1 Hz, 1H); 4.45 (s, 2H); 3.77-3.83 (m, 15 2H); 3.45-3.58 (m, 5H); 3.35-3.43 (m, 1H); 3.25 (t, J = 5.3 Hz, 2H); 3.07 (s, 3H);

2.56-2.65 (m, 1H); 1.92-2.02 (m, 1H); 1.53 (s, 3H).

MS (ESI, m/z): 544.99 [M+H⁺] for C25H29N5O7S; t_R = 0.65 min.

Example 21: (/?)-4-(6-((3-fluoro-4-(2-hydroxyacetamido)phenyl)ethynyl)-3-oxolZf-pyrrolo [1,2-c] im idazol-2(3H)-y l)-V-hy droxy-2-methyl20 2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.1 g; 0.236 mmol) and the compound of Preparation T (0.077 g; 0.26 mmol), and proceeding successively in analogy to Procedure E (39% yield) and Procedure D (68% yield), the title compound was obtained, after precipitation in water and EtOH, as an orange solid (0.032 g).

Ή NMR (%-DMSO) δ: 10.96 (d, J =1.4 Hz, 1H); 9.40-9.43 (br. s, 1H); 9.20 (d, J = 1.6 Hz, 1H); 8.05 (t, J = 8.4 Hz, 1H); 7.48 (s, 1H); 7.44 (dd, J = 1.6, 11.5 Hz, 1H); 7.33 (d, J = 8.4 Hz, 1H); 6.28 (d, J = 0.9 Hz, 1H); 5.90 (t, J = 5.9 Hz, 1H); 4.47 (s, 2H); 4.06 (d, J = 5.8 Hz, 2H); 3.46-3.54 (m, 1H); 3.35-3.46 (m, 1H); 3.07 (s, 3H); 2.58-2.65 (m, 1H); 1.93-2.02 (m, 1H); 1.54 (s, 3H).

MS (ESI, m/z): 507.0 [M+H⁺] for C22H23N4O7FS; t_R = 0.64 min.

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Example 22: (R)-/V-hy droxy-4-(6-((4-(2-hy droxyethoxy)phenyl)ethy nyl)-3-oxoIZf-pyrrolo [1,2-c] imidazol-2(3Z/)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.105 g; 0.248 mmol) and

2- (4-iodophenoxy)ethanol (0.072 g; 0.273 mmol; commercial), and proceeding successively in analogy to Procedure E (61% yield) and Procedure D (40% yield), the title compound was obtained, after precipitation in water and EtOH, as a beige solid (0.0282 g). Ή NMR (iA-DMSO) δ: 10.93-10.96 (br. s, 1H); 9.17-9.20 (br. s, 1H); 7.39-7.45 (m, 3H); 6.94-6.99 (m, 2H); 6.25 (d, J=l.lHz, 1H); 4.82-4.96 (m, 1H); 4.46 (s, 2H); 4.02 (t, J = 4.9 Hz, 2H); 3.72 (t, J = 4.9 Hz, 2H); 3.46-3.55 (m, 1H); 3.36-3.46 (overlapped m, 1H);

3.07 (s, 3H); 2.57-2.63 (m, 1H); 1.93-2.03 (m, 1H); 1.53 (s, 3H).

MS (ESI, m/z): 475.97 [M+H⁺] for C22H23N4O7FS; t_R = 0.66 min.

Example 23: (R)-/V-hydroxy-4-(6-((6-(l-(hydroxymethyl)cyclopropyl)pyridm-

3- yl)ethynyl)-3-oxo-lZ/-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)-2-methyl2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.183 g; 0.432 mmol) and the compound of Preparation U (0.131 g; 0.475 mmol), and proceeding successively in analogy to Procedure E (75% yield) and Procedure D (42% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a beige solid (0.067 g).

Ή NMR (<7>-DMSO) δ: 10.93-10.96 (br. s, 1H); 9.17-9.19 (br. s, 1H); 8.53 (d, J = 2.3 Hz,

1H); 7.80 (dd, J = 2.3, 8.4 Hz, 1H); 7.54 (d, J = 8.4 Hz, 1H); 7.48 (s, 1H); 6.28 (d,

J= 1.1 Hz, 1H); 4.79-4.84 (m, 1H); 4.46 (s, 2H); 3.75 (d, J = 3.6 Hz, 2H); 3.46-3.53 (m, 1H); 3.36-3.43 (m, 1H); 3.07 (s, 3H); 2.56-2.65 (m, 1H); 1.93-2.01 (m, 1H); 1.53 (s, 3H); 1.11-1.15 (m, 2H); 0.92-0.96 (m, 2H).

MS (ESI, m/z): 486.97 [M+H⁺] for C22H26N4O6S; t_R = 0.57 min.

Example 24: (R)-/V-hydroxy-4-(6-((5-(l-(hydroxymethyl)cyclopropyl)pyridm2-yl)ethynyl)-3-oxo-lZ/-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)-2-methyl2-(methylsulfonyl)butanamide formate:

Starting from the compound of Preparation H (0.132 g; 0.311 mmol) and the compound of Preparation V (0.105 g; 0.343 mmol), and proceeding successively in analogy to

- 136 2015226250 05 Nov 2018

Procedure E (40% yield) and Procedure D (51% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a yellow solid (0.032 g).

Ή NMR (de-DMSO) δ: 12.68-12.85 (br. s, IH, formic acid); 10.90-10.99 (br. s, IH);

9.13-9.25 (br. s, IH); 8.50 (d, J = 2.3 Hz, IH); 8.13 (s, IH, formic acid); 7.67 (dd,

J = 2.3, 8.1Hz, IH); 7.54 (s, IH); 7.46 (d, J = 8.2 Hz, IH); 6.30-6.32 (m, IH); 4.79-4.84 (m, IH); 4.47 (s, 2H); 3.54 (s, 2H); 3.46-3.52 (overlapped m, IH); 3.36-3.43 (m, IH); 3.07 (s, 3H); 2.57-2.65 (m, IH); 1.93-2.01 (m, IH); 1.53 (s, 3H); 0.87-0.91 (m, 2H); 0.82-0.86 (m, 2H).

MS (ESI, m/z): 486.99 [M+H⁺] for C23H28N4O6S; t_R = 0.55 min.

Example 25: (/?)-/V-hydroxy-2-methyl-2-(methylsulfonyl)4-(6-((4-(morpholinomethyl)phenyl)ethynyl)-3-oxo-lZZ-pyrrolo[l,2-c]imidazol2(3ZZ)-yl)butanamide:

Starting from the compound of Preparation H (0.133 g; 0.315 mmol) and

4-(4-iodobenzyl)morpholine (0.105 g; 0.347 mmol; commercial), and proceeding 15 successively in analogy to Procedure E (84% yield) and Procedure D (24% yield), the title compound was obtained, after purification by prep-HPLC (Method 1) and washing with sat. aq. NaHCCE, as a white solid (0.033 g).

Ή NMR (i/₆-DMSO) δ: 10.90-10.97 (br. s, IH); 9.15-9.21 (br. s, IH); 7.45 (s, IH);

7.44 (d, J = 8.1 Hz, 2H); 7.33 (d, J = 8.1 Hz, 2H); 6.26 (s, IH); 4.45 (s, 2H); 3.54-3.60 (m, 20 4H); 3.47-3.52 (overlapped m, IH); 3.47 (s, 2H); 3.35-3.43 (m, IH); 3.07 (s, 3H);

2.53-2.65 (m, IH); 2.29-2.39 (m, 4H); 1.94-2.02 (m, IH); 1.53 (s, 3H).

MS (ESI, m/z): 514.95 [M+H⁺] for C25H30N4O6S; t_R = 0.54 min.

Example 26: (/?)-/V-hydroxy-2-methyl-2-(methylsulfonyl)-

4-(6-((4-(l-(morpholinomethyl)cyclopropyl)phenyl)ethynyl)-3-oxo- lZZ-pyrrolo[l,2-c]imidazol-2(3ZZ)-yl)butanamide:

Starting from the compound of Preparation H (0.13 g; 0.307 mmol) and the compound of Preparation W (0.116 g; 0.338 mmol), and proceeding successively in analogy to Procedure E (39% yield) and Procedure B (40% yield), the title compound was obtained, after washing with sat. aq. NaHCCE and purification by CC (DCM-MeOH), as a yellow 30 solid (0.027 g).

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Ή NMR (ί/s-DMSO) δ: 10.92-10.96 (br. s, IH); 9.15-9.20 (br. s, IH); 7.44 (d, J = 0.8 Hz, IH); 7.31-7.38 (m, 4H); 6.25 (d, J= 1.2 Hz, IH); 4.45 (s, 2H); 3.48-3.53 (overlapped m, IH); 3.44-3.48 (m, 4H); 3.35-3.43 (m, IH); 3.07 (s, 3H); 2.55-2.62 (m, IH); 2.52 (s, 2H);

2.34-2.41 (m, 4H); 1.94-2.01 (m, IH); 1.53 (s, 3H); 0.83-0.87 (m, 2H); 0.73-0.77 (m, 2H).

MS (ESI, m/z): 555.01 [M+H⁺] for C28H34N4O6S; t_R = 0.60 min.

Example 27: (/?)-7V-hydroxy-4-(6-(((l/?,2/?)-2-(hydroxymethyl)cyclopropyl)buta- l,3-diyn-l-yl)-3-oxo-lZf-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)-2-methyl-

2- (methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.121 g; 0.286 mmol) and the 10 (7R,2R)-configurated compound of Preparation P (0.068 g; 0.315 mmol), and proceeding successively in analogy to Example 12, step 12.i (37% yield) and Procedure B (45% yield), the title compound was obtained, after purification by CC (DCM-MeOH) and trituration in Et20, as a yellow solid (0.018 g).

Ή NMR (ί/ή-DMSO) 5: 10.84-11.05 (br. s, IH); 9.02-9.20 (br. s, IH); 7.52 (s, IH); 6.23 (s, 15 IH); 4.69 (t, J = 5.8 Hz, IH); 4.42 (s, 2H); 3.43-3.51 (m, IH); 3.30-3.43 (overlapped m,

2H); 3.21-3.27 (m, IH); 3.05 (s, 3H); 2.50-2.60 (overlapped m, IH); 1.92-1.99 (m, IH); 1.51 (s, 3H); 1.35-1.43 (m, 2H); 0.87-0.91 (overlapped m, IH); 0.81-0.87 (overlapped m, IH).

MS (ESI, m/z): 433.95 [M+H⁺] for C20H23N3O6S; t_R = 0.66 min.

Example 28: (/?)-4-(6-(2-fluoro-3-methoxyphenyl)-3-oxo-lZ/-pyrrolo[l,2-c]imidazol2(3Z/)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation C (0.12 g; 0.251 mmol) and 2-fluoro-

3- methoxyphenylboronic acid (0.043 g; 0.251 mmol), and proceeding successively in analogy to Procedure A (68% yield) and Procedure B (55% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a white solid (0.041 g).

Ή NMR (500 MHz, t/₆-DMSO) 5: 10.65-11.23 (br. s, IH); 9.05-9.35 (br. s, IH); 7.47 (s, IH); 7.25-7.30 (m, IH); 7.12 (t, J = 8.1 Hz, IH); 7.03 (td, J = 0.9, 8.1Hz. IH); 6.54 (s, IH); 4.49 (s, 2H); 3.85 (s, 3H); 3.48-3.55 (m, IH); 3.36-3.44 (m, IH); 3.07 (s, 3H);

2.57-2.65 (m, IH); 1.95-2.02 (m, IH); 1.54 (s, 3H).

MS (ESI, m/z): 439.97 [M+H⁺] for C19H22N3O6FS; t_R = 0.72 min.

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Example 29: (/?)-(E)-/V-hy droxy-4-(6-(4-(hydr oxymethyljstyrylj-S-oxolZZ-pyrrolo [1,2-c] imidazol-2(3Z/)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation C (0.2 g; 0.472 mmol) and the compound of Preparation Q (0.205 g; 0.495 mmol; commercial), and proceeding successively in analogy 5 to Procedure A (51% yield), Example 15, step 15.ii (59% yield), and Procedure B (17% yield), the title compound was obtained, after purification by CC (DCM-MeOH) and prep-HPLC (Method 1), as a yellow solid (0.012 g).

Ή NMR (500 MHz, i/₆-DMSO) 5: 10.80-11.11 (br. s, IH); 9.11-9.34 (br. s, IH); 7.44 (d, J = 6.6 Hz, 2H); 7.28 (d, J = 6.6 Hz, 2H); 7.24 (s, IH); 7.08 (d, J = 16.3 Hz, IH); 6.92 (d, 10 J = 16.3 Hz, IH); 6.45 (s, IH); 5.11-5.20 (m, IH); 4.41-4.52 (m, 4H); 3.44-3.54 (s, IH);

3.30-3.42 (overlapped m, IH); 3.08 (s, 3H); 2.50-2.67 (overlapped m, IH); 1.92-2.02 (m, IH); 1.54 (s, 3H).

MS (ESI, m/z) : 448.01 [M+H⁺] for C21H25N3O6S; t_R = 0.66 min.

Example 30: (R)-V-hydroxy-4-(6-(4-(3-(hydroxymethyl)bicyclo[ 1.1.1 Jpentan15 l-yl)cyclobuta-l,3-dien-l-yl)-3-oxo-lZ/-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)-2-methyl2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.08 g; 0.189 mmol) and the compound of Preparation Y (0.087 g; 0.189 mmol; commercial), and proceeding successively in analogy to Example 12, step 12.i (31% yield), Example 15, step 15.ii (16% yield), and Procedure D 20 (10% yield) the title compound was obtained, after purification by prep-HPLC (Method 1), as a yellow solid (0.003 g).

Ή NMR (500 MHz, iA-DMSO) 5: 10.56-11.42 (br. s, IH); 9.07-9.26 (br. s, IH); 7.56 (s, IH); 6.24-6.26 (m, IH); 4.58 (t, J = 5.6 Hz, IH); 4.43 (s, 2H); 3.45-3.53 (m, IH);

3.37-3.43 (m, IH); 3.30-3.35 (overlapped m, 2H); 3.06 (s, 3H); 2.50-2.61 (overlapped m, 25 IH); 1.91-1.99 (m, 7H); 1.52 (s, 3H).

MS (ESI, m/z): 459.98 [M+H⁺] for C22H25N3O6S; t_R = 0.70 min.

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Example 31: (R)-4-(6-(5-ammo-5-methylhexa-l,3-diyn-l-yl)-3-oxoΙΖΖ-pyrrolo [1,2-c] im idazol-2(3H)-y l)-V-hy droxy-2-methyl-

2- (methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.2 g; 0.472 mmol) and the compound of

Preparation Z (0.124 g; 0.592 mmol), and proceeding successively in analogy to Procedure G (48% yield) and Procedure D (15% yield), the title compound was obtained, after washing with sat. aq. NaHCCL and purification by CC (DCM-MeOH), as a yellow solid (0.01 g).

Ή NMR (500 MHz, rL-DMSO) 5: 10.32-11.39 (br. s, IH); 9.08-9.34 (br. s, IH); 7.56 (s,

IH); 6.25 (d, J = 1.2 Hz, IH); 4.43 (s, 2H); 3.44-3.56 (m, IH); 3.35-3.44 (m, IH); 3.06 (m, 3H); 2.54-2.63 (m, IH); 1.91-2.04 (m, IH); 1.53 (s, 3H); 1.35 (s, 6H).

MS (ESI, m/z): 421.82 [M+H⁺] for C19H24N4O5S; t_R = 0.51 min.

Example 32: (R)-4-((2-(4-(hydroxyammo)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-

3- oxo-2,3-dihydro-lZZ-pyrrolo[l,2-c]imidazol-6-yl)ethynyl)benzyl carbamate:

Starting from the compound of Preparation H (0.15 g; 0.354 mmol) and the compound of Preparation AA (0.147 g; 0.531 mmol) and proceeding successively in analogy to Procedure E (71% yield) and Procedure H (49% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a beige solid (0.06 g).

'HNMR (500 MHz, rL-DMSO) 5: 10.95 (s, IH); 9.19 (s, IH); 7.47-7.51 (m, 3H); 7.37 (d,

J = 8.4 Hz, 2H); 6.52-6.86 (m, 2H); 6.28 (d, J = 1.2 Hz, IH); 5.00 (s, 2H); 4.47 (s, 2H);

3.46-3.56 (m, IH); 3.36-3.44 (m, IH); 3.08 (s, 3H); 2.56-2.65 (m, IH); 1.92-2.04 (m, IH); 1.49-1.58 (m, 3H).

MS (ESI, m/z):488.97 for C22H24N4O7S; t_R = 0.68 min.

Example 33: (R)-4-(6-(((lS,3R,4S)-3,4-dihydroxycyclopentyl)buta-l,3-diyn-l-yl)25 3-oxo-lZZ-pyrrolo[l,2-c]imidazol-2(3ZZ)-yl)-/V-hydroxy-2-methyl2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.1 g; 0.236 mmol) and the compound of Preparation AB (0.087 g; 0.35 mmol), and proceeding successively in analogy to

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Example 12, step 12.i (72% yield) and Procedure H (14% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a beige solid (0.008 g).

Ή NMR (d6-DMSO) 5: 10.83 (br. s, IH); 8.72 (br. s, IH); 7.53 (s, IH); 6.23 (s, IH);

4.56 (d, J = 1.9 Hz, 2H); 4.43 (s, 2H); 4.11 (d, J = 4.2 Hz, IH); 3.95 (s, 2H); 3.43-3.53 (m,

IH); 3.29-3.42 (m, IH); 3.08-3.15 (m, IH); 3.05 (s, 3H); 1.83-2.01 (m, 3H); 1.72-1.82 (m, 2H); 1.44 (s, 3H).

MS (ESI, m/z): 463.97 for C21H25N3O7S; t_R = 0.60 min.

Example 34: (/?)-(1 -(4-((2-(4-(hydroxyammo)-3-methyl-3-(methylsulfonyl)-

4-oxobutyl)-3-oxo-2,3-dihydro-lZ7-pyrrolo[l,2-c]imidazol-

6-yl)ethynyl)phenyl)cyclopropyl)methyl carbamate:

Starting from the compound of Preparation H (0.15 g; 0.354 mmol) and the compound of Preparation AC (0.168 g; 0.531 mmol) and proceeding successively in analogy to Procedure E (70% yield) and Procedure D (63% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a white solid (0.06 g).

Ή NMR (Λ-DMSO) 5: 10.95 (br. s, IH); 9.19 (s, IH); 7.45 (d, J = 0.8Hz, IH); 7.39-7.43 (m, 2H); 7.27-7.32 (m, 2H); 6.30-6.71 (m, 2H); 6.27 (d, J =1.2 Hz, IH);

4.43-4.49 (m, 2H); 4.11 (s, 2H); 3.46-3.57 (m, IH); 3.36-3.45 (m, IH); 3.08 (s, 3H);

2.58-2.64 (m, IH); 1.94-2.03 (m, IH); 1.54 (s, 3H); 0.97-1.02 (m, 2H); 0.89-0.94 (m, 2H). MS (ESI, m/z):529.02 for C25H28N4O7S; t_R = 0.74 min.

Example 35: (/?)-(l-((2-(4-(hydroxyammo)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-

3-oxo-2,3-dihydro-lZ/-pyrrolo[l,2-c]imidazol-6-yl)buta-l,3-diyn- l-yl)cyclopropyl)methyl carbamate:

Starting from the compound of Preparation H (0.18 g; 0.425 mmol) and the compound of

Preparation AD (0.13 g; 0.595 mmol) and proceeding successively in analogy to 25 Example 12, step 12.i (80% yield) and Procedure D (71% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as a yellow solid (0.116 g).

Ή NMR (Λ-DMSO) 5: 10.78-11.22 (br. s, IH); 8.99-9.45 (br. s, IH); 7.56 (s, IH);

6.36-6.95 (m, 2H); 6.25 (d, J= 1.1 Hz, IH); 4.43 (s, 2H); 3.88 (s, 2H); 3.45-3.54 (m, IH);

3.34-3.43 (m, IH); 3.06 (s, 3H); 2.55-2.66 (m, IH); 1.92-2.02 (m, IH); 1.53 (s, 3H); 30 0.96-1.06 (m,4H).

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2015226250 05 Nov 2018

MS (ESI, m/z): 476.97 for C21H24N4O7S; t_R = 0.66 min.

Example 36: (R)-A-hydroxy-4-(6-(((7R,2R)-2-(hydroxymethyl)-

1- methylcyclopropyl)buta-l,3-diyn-l-yl)-3-oxo-lZZ-pyrrolo[l,2-c]imidazol-2(3ZZ)-yl)-

2- methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.207 g; 0.49 mmol) and the compound of Preparation AE (0.313 g; 0.73 mmol) and proceeding successively in analogy to Example 12, step 12.i (72% yield), Example 15, step 15.ii (80% yield) and Procedure D (72% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as a white solid (0.091 g).

Ή NMR (i/s-DMSO) 5: 10.58-11.23 (br. s, 1H); 9.04-9.44 (br. s, 1H); 7.52 (d, J = 1.0 Hz, 1H); 6.23 (d, J =1.0 Hz, 1H); 4.67 (t, J = 5.3 Hz, 1H), 4.43 (s, 2H); 3.57-3.65 (m, 1H);

3.35-3.43 (m, 1H); 3.23-3.30 (m, 1H); 3.06 (s, 3H); 2.55-2.64 (m, 1H); 1.91-2.01 (m, 1H);

1.53 (s, 3H); 1.36-1.43 (m, 1H); 1.29 (s, 3H); 1.08 (dd, J = 4.4, 9.2 Hz, 1H); 0.61 (dd, J = 4.6, 6.6 Hz, 1H).

MS (ESI, m/z): 448.03 for C21H25N3O6S; t_R = 0.69 min.

Example 37: (R)-(l-(4-((2-(4-(hydroxyammo)-3-methyl-3-(methylsulfonyl)4-oxobutyl)-3-oxo-2,3-dihydro-lZZ-pyrrolo[l,2-c]imidazol-

6-yl)ethynyl)phenyl)cyclopropyl)methyl dimethylglycinate hydrochloride:

Starting from the compound of Preparation H (0.2 g; 0.472 mmol) and the compound of 20 Preparation AF (0.217 g; 0.604 mmol) and proceeding successively in analogy to

Procedure E (36% yield) and Procedure D (28% yield), the title salt was obtained, after purification by prep-HPLC (Method 2) and lyophilisation in HCI IM, as a yellow lyophilisate (0.027 g).

Ή NMR (ί/s-DMSO) 5: 10.94-10.96 (br. s, 1H); 9.94-10.08 (br. s, 1H); 9.17-9.21 (br. s,

1H); 7.45 (d, J = 0.8Hz, 1H); 7.41-7.45 (m, 2H); 7.31-7.36 (m, 2H); 6.25-6.28 (m, 1H);

4.45-4.48 (m, 2H), 4.36-4.39 (m, 2H); 4.08-4.22 (m, 2H); 3.47-3.56 (m, 1H); 3.36-3.45 (m, 1H); 3.08 (s, 3H); 2.78 (s, 6H); 2.57-2.64 (m, 1H); 1.94-2.03 (m, 1H); 1.54 (s, 3H); 1.04-1.10 (m, 2H); 0.97-1.01 (m, 2H).

MS (ESI, m/z): 571.01 for C28H35N4O7CIS; t_R = 0.63 min.

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Example 38: (/?)-4-(6-((l-ammocyclopropyl)buta-l,3-diyn-l-yl)-3-oxol//-pyrrolo[l,2-c]imidazol-2(3//)-yl)-V-hydroxy-2-methyl-

2- (methylsulfonyl)butanamide hydrochloride:

Preparation AG (0.115g; 0.472 mmol) and proceeding successively in analogy to Procedure G (49% yield) and Procedure H (22% yield), the title salt was obtained, after purification by prep-HPLC (Method 2) and lyophilisation in \M HCI, as a pale beige lyophilisate (0.023 g).

Ή NMR (WDMSO) 5: 10.93-10.95 (br. s, 1H); 9.16-9.19 (br. s, 1H); 8.65-8.99 (m, 3H);

7.66 (s, 1H); 6.30 (d, J = 1.2 Hz, 1H); 4.44 (s, 2H); 3.45-3.54 (m, 1H); 3.36-3.45 (m, 1H);

3.06 (s, 3H); 2.54-2.62 (m, 1H); 1.92-2.02 (m, 1H); 1.53 (s, 3H); 1.32-1.43 (m, 4H). MS (ESI, m/z): 419.09 for C19H23N4O5CIS; t_R = 0.49 min.

Example 39: (/?)-4-(6-((3-aminooxetan-3-yl)buta-l,3-diyn-l-yl)-3-oxo1//-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-V-hydroxy-2-methyl15 2-(methylsulfonyl)butanamide hydrochloride:

Starting from the compound of Preparation H (0.15 g; 0.354 mmol) and the compound of Preparation AH (0.148 g; 0.46 mmol) and proceeding successively in analogy to Procedure G (53% yield) and Procedure H (40% yield), the title salt was obtained, after purification by prep-HPLC (Method 2) and lyophilisation in \M HCI, as a pale beige 20 lyophilisate (0.036 g).

Ή NMR (WDMSO) 5: 10.93-10.96 (br. s, 1H); 9.16-9.19 (br. s, 1H); 8.97-9.15 (m, 3H); 7.71 (s, 1H); 6.33 (s, 1H); 4.74-4.82 (m, 4H); 4.52 (s, 2H); 3.45-3.53 (m, 1H);

3.36-3.44 (m, 1H); 3.06 (s, 3H); 2.56-2.62 (m, 1H); 1.93-2.01 (m, 1H); 1.52 (s, 3H).

MS (ESI, m/z+MeCN): 476.04 for C19H23N4O6CIS; t_R = 0.47 min.

Example 40: (R)- V-hydroxy-4-(6-((4-(l-(hydroxymethyl)cyclobutyl)phenyl)ethynyl)-

3- oxo-///-pyrrolo[l,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.062 g; 0.146 mmol) and the compound of Preparation Al (0.063 g; 0.22 mmol) and proceeding successively in analogy to

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Procedure E (67% yield) and Procedure B (40% yield), the title compound was obtained, after purification by CC (DCM-MeOH), as an off-white solid (0.018 g).

Ή NMR (ok-DMSO) 5: 10.92-10.98 (br. s, IH); 9.17-9.22 (br. s, IH); 7.44 (s, IH);

7.40 (d, J = 8.2 Hz, 2H); 7.13 (d, J = 8.2 Hz, 2H); 6.26 (d, J =1.0 Hz, IH); 4.78 (t,

J = 5.5 Hz, IH); 4.45 (s, 2H); 3.46-3.54 (overlapped m, IH); 3.51 (overlapped d,

J = 5.5 Hz, 2H); 3.35-3.43 (m, IH); 3.07 (s, 3H); 2.57-2.63 (m, IH); 2.12-2.25 (m, 4H); 1.94-2.02 (m, 2H); 1.72-1.81 (m, IH); 1.53 (s, 3H).

MS (ESI, m/z): 500.03 for C25H29N3O6S; t_R = 0.68 min.

Example 41: (/?)-4-(6-(2-fluoro-4-(2-hydroxyethoxy)phenyl)-3-oxo10 1 //-pyrrolo[ 1,2-c] imidazol-2(3//)-yl)-V-hydroxy-2-methyl2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation C (0.198 g; 0.414 mmol) and the compound of Preparation AJ (0.134 g; 0.474 mmol) and proceeding successively in analogy to Procedure A (43% yield) and Procedure B (17% yield), the title compound was obtained, 15 after purification by prep-HPLC (Method 1), as a yellow solid (0.014 g).

Ή NMR (i/₆-DMSO) 5: 10.95 (br. s, IH); 9.19 (br. s, IH); 7.62 (t, J = 9.0 Hz, IH); 7.37 (s, IH); 6.88 (dd, J = 2.5, 13.4 Hz, IH); 6.81 (dd, J = 2.4, 8.7 Hz, IH); 6.50 (s, IH); 4.89 (t, J = 5.5 Hz, IH); 4.48 (s, 2H); 4.01 (t, J = 4.8 Hz, 2H); 3.71 (q, J = 5.2 Hz, 2H); 3.51 (m, IH); 3.39 (m, IH); 3.07 (s, 3H); 2.60 (m, IH); 1.98 (m, IH); 1.54 (s, 3H).

MS (ESI, m/z): 469.98 [M+H⁺] for C20H24N3O7ES; t_R = 0.62 min.

Example 42: (/?)-4-(6-(((2/?,35)-2,3-bis(hydroxymethyl)cyclopropyl)buta-l,3-diyn-

1- yl)-3-oxo-lZ7-pyrrolo[l,2-c]imidazol-2(3ZZ)-yl)-/V-hydroxy-2-methyl-

2- (methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.1 g; 0.236 mmol) and the compound of 25 Preparation AK (0.089 g; 0.354 mmol) and proceeding successively in analogy to

Procedure G (82% yield) and Procedure D (14% yield), the title compound was obtained, after purification by prep-HPLC (Method 1) and CC (DCM-MeOH), as a yellow solid (0.011 g).

Ή NMR (i/₆-DMSO) 5: 10.94 (s, IH); 9.19 (s, IH); 7.54 (s, IH); 6.23-6.26 (m, IH); 30 4.64-4.69 (m, 2H); 4.43 (s, 2H); 3.35-3.56 (m, 5H); 3.23-3.28 (m, IH); 3.06 (s, 3H);

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2.55 (m, IH); 1.96 (m, IH); 1.60 (dd, J = 4.8, 8.1Hz, IH); 1.52 (s, 3H); 1.28 (m, IH);

1.18 (m, IH).

MS (ESI, m/z): 463.97 [M+H⁺] for C21H25N3O7S; t_R = 0.57 min.

Example 43: (/?)-4-(6-(4-((/?)-2,3-dihydroxypropoxy)-2-fluorophenyl)-3-oxo5 l//-pyrrolo[l,2-c]imidazol-2(3//)-yl)-V-hydroxy-2-methyl2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation C (0.11 g; 0.234 mmol) and the compound of Preparation AM (0.082 g; 0.232 mmol) and proceeding successively in analogy to Procedure A (36% yield) and Procedure B (17% yield), the title compound was obtained, 10 after purification by prep-HPLC (Method 1), as a white solid (0.007 g).

Ή NMR (i/₆-DMSO) 5: 10.97 (br. s, IH); 9.19 (br s, IH); 7.62 (t, J = 9.0 Hz, IH); 7.37 (s, IH); 6.87 (dd, J = 2.4, 13.4 Hz, IH); 6.81 (dd, J = 2.4, 8.7 Hz, IH); 6.50 (s, IH); 4.98 (d, J = 5.1Hz, IH); 4.69 (t, J = 5.7Hz, IH); 4.48 (s, 2H); 4.03 (dd, J = 4.0, 10.1 Hz, IH); 3.89 (dd, J = 6.2, 10.1 Hz, IH); 3.79 (m, IH); 3.52 (m, IH); 3.44 (t, J = 5.7 Hz, 2H);

3.39 (m, IH); 3.07 (s, 3H); 2.60 (m, IH); 1.99 (m, IH); 1.52 (s, 3H).

MS (ESI, m/z): 499.98 [M+H⁺] for C21H26N3O8ES; t_R = 0.58 min.

Example 44: (/?)-4-(6-((4-(l,l-difluoro-2-hydroxyethyl)phenyl)ethynyl)-3-oxol//-pyrrolo[l,2-c]imidazol-2(3//)-yl)-V-hydroxy-2-methyl2-(methylsulfonyl)butanamide:

44.i. (2R)-4-(6-((4-(l,l-difluoro-2-hydroxyethyl)phenyl)ethynyl)-3-oxolH-pyrrolo[l,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro2H-pyran-2-yl)oxy)butanamide:

Starting from the compound of Preparation H (0.08 g; 0.19 mmol) and the compound of Preparation Al (0.054 g; 0.19 mmol) and proceeding in analogy to Procedure E, the title 25 compound was obtained, after purification by CC (Hept-EA), as a yellow solid (0.030 g;

27% yield).

MS (ESI, m/z): 580.0 for C27H31N3O7E2S; t_R = 0.82 min.

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44. ii. (R)-4-(6-((4-(1, l-difluoro-2-hydroxyethyl)phenyl)ethynyl)-3-oxolH-pyrrolo[ 1,2-c] imidazol-2(3H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide:

To a solution of intermediate 44. i (0.0301 g; 0.06 mmol) in EtOH (1 mL) was added Amberlyst 15 (0.030 g). The mixture was stirred 1 h at 80°C. The ethanol was evaporated and the mixture was taken in DMF (2 mL). The solids were filtered and the filtrate was evaporated. The residue was purified by prep-HPLC (Method 3) to afford the title compound as an off-white solid (0.0076 g; 30% yield).

Ή NMR (<A-DMSO) 5: 7.59 (m, 2H); 7.54 (m, 2H); 7.51 (d, J = 0.6 Hz, 1H); 6.30 (d, J = 1.2 Hz, 1H); 5.66 (t, J = 6.3 Hz, 1H); 4.46 (s, 2H); 3.86 (m, 2H); 3.47-3.54 (m, 1H);

3.40 (m, 1H); 3.07 (s, 3H); 2.60 (m, 1H); 1.97 (m, 1H); 1.53 (s, 3H).

MS (ESI, m/z): 495.98 [M+H⁺] for C22H23N3O6F2S; t_R = 0.71 min.

Example 45: (/?)-V-hydroxy-4-(6-((4-(2-hydroxyacetyl)phenyl)ethynyl)-3-oxo1//-pyrrolo[ l,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.07 g; 0.165 mmol) and 2-hydroxy15 l-(4-iodophenyl)ethan-l-one (0.044 g; 0.166 mmol) and proceeding successively in analogy to Procedure E (27% yield) and Example 44, step 44.H (28 % yield), the title compound was obtained, after purification by prep-HPLC (Method 3), as a brownish solid (0.006 g).

Ή NMR (ί/s-DMSO) 5: 10.96 (s, 1H); 9.19 (br. s, 1H); 7.94 (m, 2H); 7.62 (m, 2H);

7.55 (d, J = 0.8 Hz, 1H); 6.32 (d, J = 1.2 Hz, 1H); 5.15 (br. s, 1H); 4.80 (s, 2H); 4.48 (s,

2H); 3.51 (m, 1H); 3.41 (m, 1H); 3.08 (s, 3H); 2.61 (m, 1H); 1.99 (m, 1H); 1.54 (s, 3H). MS (ESI, m/z): 473.95 [M+H⁺] for C22H23N3O7S; t_R = 0.71 min.

Example 46: (/?)-4-(6-(5-(dimethylamino)penta-l ,3-diyn-l-yl)-3-oxolZZ-pyrrolo[l,2-c]imidazol-2(3ZZ)-yl)-/V-hydroxy-2-methyl25 2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.08 g; 0.19 mmol) and the compound of Preparation AJ (0.04 g; 0.19 mmol) and proceeding successively in analogy to Procedure E (26% yield) and Example 44, step 44.H (29% yield), the title compound was obtained, after purification by prep-HPLC (Method 3), as a brownish solid (0.006 g).

- 146 2015226250 05 Nov 2018

Ή NMR (ζ/ά-DMSO) δ: 10.93 (br. s, 1H); 9.17 (br. s, 1H); 7.59 (s, 1H); 6.28 (m, 1H); 4.43 (s, 2H); 3.49 (s, 2H); 3.48 (partially overlapped m, 1H); 3.06 (s, 3H); 2.98-3.02 (m, 1H); 2.56-2.61 (overlapped m, 1H); 2.20-2.26 (m, 6H); 1.52 (s, 3H); 1.52 (partially overlapped m, 1H).

MS (ESI, m/z): 420.96 [M+H⁺] for C19H24N4O5S; t_R = 0.49 min.

Example 47: methyl (7?)-3-fluoro-4-(2-(4-(hydroxyammo)-3-methyl3-(methylsulfonyl)-4-oxobutyl)-3-oxo-2,3-dihydro-l/Z-pyrrolo[l,2-c]imidazol6-yl)benzoate:

Starting from the compound of Preparation C (0.150 g; 0.314 mmol) and 2-fluoro10 4-(methoxycarbonyl)phenylboronic acid (0.062 g; 0.313 mmol) and proceeding successively in analogy to Procedure A (34% yield) and Procedure B (23% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a white solid (0.012 g).

Ή NMR (z/6-DMSO) 5: 10.94 (br. s, 1H); 9.20 (br. s, 1H); 7.94 (m, 1H); 7.79 (d, 15 J = 8.1 Hz, 1H); 7.75 (d, J = 11.9 Hz, 1H); 7.64 (s, 1H); 6.67 (s, 1H); 4.53 (s, 2H); 3.88 (s, 3H); 3.49-3.55 (overlapped m, 1H); 3.40-3.46 (overlapped m, 1H); 3.08 (s, 3H);

2.60-2.63 (overlapped m, 1H); 1.97-2.04 (m, 1H); 1.55 (s, 3H).

MS (ESI, m/z): 467.93 [M+H⁺] for C20H22N3O7FS; t_R = 0.73 min.

Example 48: (7?)-4-(6-(4-chloro-2-fluorophenyl)-3-oxo-l/Z-pyrrolo[l,2-c]imidazol20 2(3//)-yl)-V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation C (0.150 g; 0.314 mmol) and 4-chloro2-fluorophenylboronic acid (0.055 g; 0.315 mmol) and proceeding successively in analogy to Procedure A (66% yield) and Procedure B (33% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a white solid (0.031 g).

Ή NMR (z/6-DMSO) 5: 10.88-11.00 (br. s, 1H); 9.12-9.23 (br. s, 1H); 7.78 (t, J = 8.5 Hz, 1H); 7.51 (s, 1H); 7.48 (dd, J= 1.8, 11.2 Hz, 1H); 7.30 (dd, J= 1.7, 8.4 Hz, 1H); 6.58 (s, 1H); 4.50 (s, 2H); 3.48-3.55 (m, 1H); 3.38-3.44 (overlapped m, 1H); 3.07 (s, 3H); 2.57-2.62 (overlapped m, 1H); 1.95-2.02 (m, 1H); 1.54 (s, 3H).

MS (ESI, m/z): 443.93 [M+H⁺] for C18H19N3O5CIFS; t_R = 0.77 min.

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Example 49: (7?)-4-(6-(2-chloro-4-ethoxyphenyl)-3-oxo-lZZ-pyrrolo[l,2-c]imidazol2(3ZZ)-yl)-/V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation C (0.150 g; 0.314 mmol) and 2-chloro4-ethoxyphenylboronic acid (0.063 g; 0.314 mmol) and proceeding successively in analogy 5 to Procedure A (74% yield) and Procedure B (28% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a white solid (0.031 g).

Ή NMR (rt6-DMSO) 5: 10.87-10.99 (br. s, 1H); 9.16-9.22 (br. s, 1H); 7.46 (d, J = 8.6 Hz, 1H); 7.36 (s, 1H); 7.06 (d, J = 2.6 Hz, 1H); 6.93 (dd, J = 2.6, 8.6 Hz, 1H); 6.40 (s, 1H);

4.48 (s, 2H); 4.01-4.10 (m, 2H); 3.46-3.56 (overlapped m, 1H); 3.07 (s, 3H);

2.57-2.62 (overlapped m, 1H); 1.98 (overlapped m, 1H); 1.54 (s, 3H); 1.33 (t, J = 6.9 Hz,

3H).

MS (ESI, m/z): 469.92 [M+H⁺] for C20H24N3O6CIS; t_R = 0.77 min.

Example 50: (7?)-(l-((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)3-oxo-2,3-dihydro-lZZ-pyrrolo[l,2-c]imidazol-6-yl)buta-l,3-diyn15 l-yl)cyclopropyl)methyl dimethylglycinate hydrochloride:

Starting from the compound of Preparation H (0.38 g; 0.89 mmol) and the compound of

Preparation AP (0.303 g; 1.17 mmol) and proceeding successively in analogy to Example 12, step 12.i (66% yield) and Procedure D (37% yield), the title compound was obtained, after purification by prep-HPLC (Method 2) and lyophilisation from \M HCI, as 20 a white foam (0.12 g).

Ή NMR (rt6-DMSO) 5: 10.94 (m, 1H); 10.41 (m, 1H); 9.20 (m, 1H); 7.57 (d, J = 0.8 Hz, 1H); 6.24 (d, J =1.2 Hz, 1H); 4.44 (m, 2H); 4.31 (m, 2H); 4.17 (m, 2H); 3.48 (m, 1H); 3.30-3.43 (overlapped m, 1H); 3.06 (s, 3H); 2.86 (s, 6H); 2.59 (m, 1H); 1.96 (m, 1H);

1.53 (s, 3H); 1.08-1.14 (m, 4H).

MS (ESI, m/z): 519.0 [M+H⁺] for C24H30N4O7S; t_R = 0.59 min.

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Example 51: (/?)-(l-((2-(4-(hydroxyammo)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-

3- oxo-2,3-dihydro-lZZ-pyrrolo[l,2-c]imidazol-6-yl)buta-l,3-diyn-

1- yl)cyclopropyl)methyl dihydrogen phosphate:

Starting from the compound of Preparation H (0.3 g; 0.7 mmol) and the compound of

Preparation AQ (0.338 g; 0.92 mmol) and proceeding successively in analogy to Example 12, step 12.i (84% yield) and Procedure I (59% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a white foam (0.13 g).

Ή NMR (ί/6-DMSO) 5: 10.94 (s, IH); 9.19 (s, IH); 7.56 (d, J = 0.8 Hz, IH); 6.25 (d, J =1.2 Hz, IH); 4.43 (s, 2H); 3.74 (d, J = 6.1 Hz, 2H); 3.45-3.53 (m, 2H);

3.22-3.43 (overlapped m, 2H); 3.06 (s, 3H); 2.59 (m, IH); 1.96 (m, IH); 1.53 (s, 3H);

0.98-1.07 (m, 4H).

MS (ESI, m/z): 513.9 [M+H⁺] for C20H24N3O9PS; t_R = 0.56 min.

Example 52: (/?)-4-(6-(2-chloro-4-methoxyphenyl)-3-oxo-lZZ-pyrrolo[l,2-c]imidazol2(3//)-yl)-V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation C (0.150 g; 0.314 mmol) and 2-chloro-

4- methoxyphenylboronic acid (0.059 g; 0.317 mmol) and proceeding successively in analogy to Procedure A (58% yield) and Procedure B (35% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a white solid (0.029 g).

Ή NMR (ί/6-DMSO) 5: 10.97 (br.s, IH); 9.22 (br.s, IH); 7.49 (d, J = 8.7 Hz, IH);

7.38 (s, IH); 7.09 (d, J = 2.5 Hz, IH); 6.96 (dd, J = 2.5, 8.7 Hz, IH); 6.41 (d, J = 0.9 Hz,

IH); 4.49 (s, 2H); 3.80 (s, 3H); 3.49-3.56 (m, IH); 3.38-3.42 (overlapped m, IH); 3.08 (s, 3H); 2.58-2.63 (overlapped m, 2H); 1.96-2.03 (m, IH); 1.55 (s, 3H).

MS (ESI, m/z): 455.93 [M+H⁺] for C19H22N3O6CIS; t_R = 0.77 min.

Example 53: (/?)-4-(6-(2-fluoro-4-(trifluoromethyl)phenyl)-3-oxo25 1//-pyrrolo[ 1,2-c] imidazol-2(3//)-yl)-V-hydroxy-2-methyl-

2- (methylsulfonyl)butanamide:

Starting from the compound of Preparation C (0.150 g; 0.314 mmol) and (2-fluoro-

4-(trifluoromethyl)phenyl)boronic acid (0.065 g; 0.317 mmol) and proceeding successively

- 149 -

2015226250 05 Nov 2018 in analogy to Procedure A (62% yield) and Procedure B (26% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a white solid (0.014 g).

Ή NMR (ί/6-DMSO) 5: 10.96 (s, 1H), 9.20 (s, 1H), 8.00 (t, J = 7.9 Hz, 1H), 7.73 (d,

J = 11.4 Hz, 1H), 7.65 (s, 1H), 7.59 (d, J = 8.7 Hz, 1H), 6.67 (s, 1H), 4.53 (s, 2H),

3.50-3.57 (m, 1H), 3.39-3.46 (overlapped m, 1H), 3.08 (s, 3H), 2.59-2.66 (overlapped m,

1H), 1.97-2.04 (m, 1H), 1.55 (s, 3H).

MS (ESI, m/z): 477.92 [M+H⁺] for C19H19N3O5F4S; t_R = 0.80 min.

Example 54: (/?)-V-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo6-(2,3,4-trifluorophenyl)-lZ/-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)butanamide:

Starting from the compound of Preparation C (0.200 g; 0.418 mmol) and (2,3,4-trifluorophenyl)boronic acid (0.073 g; 0.415 mmol) and proceeding successively in analogy to Procedure A (32% yield) and Procedure B (25% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a white solid (0.015 g).

Ή NMR (ί/6-DMSO) 5: 10.96 (br. s, 1H); 9.20 (br. s, 1H); 7.57-7.63 (m, 1H); 7.55 (s, 1H); 15 7.31-7.38 (m, 1H); 6.58 (s, 1H); 4.51 (s, 2H); 3.49-3.56 (m, 1H); 3.38-3.45 (m, 1H);

3.08 (s, 3H); 2.59-2.63 (overlapped m, 1H); 1.96-2.03 (m, 1H); 1.55 (s, 3H).

MS (ESI, m/z): 445.88 [M+H⁺] for CisHigNsOjFsS; t_R = 0.76 min.

Example 55: (/?)-4-(6-(2,3-difluoro-4-methoxyphenyl)-3-oxo1//-pyrrolo[ 1,2-c] imidazol-2(3//)-yl)-V-hydroxy-2-methyl20 2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation C (0.150 g, 0.314 mmol) and (2,3-difluoro-

4-methoxyphenyl)boronic acid (0.059 g, 0.314 mmol) and proceeding successively in analogy to Procedure A (48% yield) and Procedure B (65% yield), the title compound was obtained, after purification by prep-HPLC (Method 1) to afford the title compound (0.045 25 g) as a white solid.

Ή NMR (ί/6-DMSO) 5: 10.96 (d, J =1.7 Hz, 1H); 9.20 (d, J =1.8 Hz, 1H); 7.49 (td, J = 2.2, 8.8 Hz, 1H); 7.45 (s, 1H); 7.05 (m, 1H); 6.53 (s, 1H); 4.50 (s, 2H); 3.90 (s, 3H); 3.49-3.55 (m, 1H); 3.37-3.44 (m, 1H); 3.08 (s, 3H); 2.59-2.63 (overlapped m, 1H);

1.96-2.02 (m, 1H); 1.55 (s, 3H).

MS (ESI, m/z): 457.93 [M+H⁺] for C19H21N3O6F2S; t_R=0.74 min.

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Example 56: (/?)-N-hydroxy-4-(6-((l-(hydroxymethyl)cyclobutyl)buta-l,3-diyn-l-yl)-

3-oxo-lZ7-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.1 g; 0.23 mmol) and the compound of Preparation AS (0.131 g; 0.3 mmol), and proceeding successively in analogy to

Example 12, step 12.i (63% yield), Example 15, step 15.ii (92% yield) and Procedure D (52% yield), the title compound was obtained, after precipitation from water and drying, as a yellowish solid (0.033 g).

’H NMR (ί/6-DMSO) 5: 10.90 (br. s, 1H); 9.19 (br. s, 1H); 7.55 (d, J =1.0 Hz, 1H);

6.25 (m, 1H); 5.15 (t, J = 5.8 Hz, 1H); 4.43 (s, 2H); 3.45-3.53 (m, 3H); 3.37-3.43 (m, 1H);

3.07 (s, 3H); 2.56-2.63 (m, 1H); 2.07-2.17 (m, 4H); 1.84-2.01 (m, 3H); 1.53 (s, 3H).

MS (ESI, m/z): 448.00 [M+H⁺] for C21H25N3O6S; t_R = 0.70 min.

Example 57: ((/?)-V-hydroxy-4-(6-((3-(hydroxy methy l)oxetan-3-y l)buta-1,3-diy n-

1- yl)-3-oxo-lZ7-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)-2-methyl-

2- (methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.1 g; 0.23 mmol) and the compound of Preparation AT (0.132 g; 0.3 mmol), and proceeding successively in analogy to Example 12, step 12.i (60% yield), Example 15, step 15.ii (92% yield) and Procedure D (44% yield), the title compound was obtained, after precipitation from water and drying, as a yellowish solid (0.026 g).

Ή NMR (ί/6-DMSO) 5: 10.9 (br. s, 1H); 9.19 (br. s, 1H); 7.59 (m, 1H); 6.28 (m, 1H);

5.46 (t, J = 5.9 Hz, 1H); 4.58 (d, J = 5.7 Hz, 2H); 4.52 (d, J = 5.7 Hz, 2H); 4.44 (s, 2H); 3.70 (d, J = 5.9 Hz, 2H); 3.49 (m, 1H); 3.38 (m, 1H); 3.07 (s, 3H); 2.60 (m, 1H); 1.93 (m, 1H); 1.53 (s, 3H).

MS (ESI, m/z): 450.00 [M+H⁺] for C20H23N3O7S; t_R = 0.61 min.

Example 58: (/?)- V-hydroxy-2-methyl-4-(6-(5-(methylsulfonamido)penta-l,3-diynl-yl)-3-oxo-lZ/-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.280 g; 0.754 mmol) and the compound of Preparation BM (0.246 g; 0.58 mmol), and proceeding successively in analogy to

- 151 2015226250 05 Nov 2018

Example 12, step 12.i (84% yield) and Procedure D (65% yield), the title compound was obtained, after precipitation and drying, as a greyish solid (0.08 g).

'H NMR (ί/6-DMSO) 5: 10.91 (s, 1H); 9.15 (s, 1H); 7.67 (t, J = 6.0 Hz, 1H); 7.62 (d,

J = 0.7 Hz, 1H); 6.29 (d, J = 1.2 Hz, 1H); 4.44 (s, 2H); 4.04 (d, J = 5.9 Hz, 2H); 3.48 (m, 5 1H); 3.38 (m, 1H); 3.06 (s, 3H); 2.98 (s, 3H); 2.58 (m, 1H); 1.96 (m, 1H); 1.52 (s, 3H).

MS (ESI, m/z) : 471.0 [M+H⁺] for C18H22N4O7S2; t_R = 0.63 min.

Example 59: tert-butyl (/?)-3-hydroxy-3-(4-((2-(4-(hydroxyammo)-3-methyl-

3-(methylsulfonyl)-4-oxobutyl)-3-oxo-2,3-dihydro-lZ/-pyrrolo[l,2-c]imidazol6-yl)ethynyl)phenyl)azetidine-l-carboxylate:

Starting from the compound of Preparation H (0.246 g; 0.58 mmol) and the compound of Preparation BK (0.283 g; 0.76 mmol), and proceeding successively in analogy to Procedure E (70% yield) and Procedure D (35% yield), the title compound was obtained, after purification by prep-HPLC (Method 3), as a yellowish solid (0.024 g).

Ή NMR (ί/6-DMSO) 5: 9.20 (br. s, 1H); 7.47-7.56 (m, 4H); 7.47 (d, J = 0.6 Hz, 1H); 15 6.43 (s, 1H); 6.28 (d, J= 1.2 Hz, 1H); 4.47 (s, 2H); 4.03 (s, 4H); 3.50 (m, 1H); 3.39 (m,

1H); 3.08 (s, 3H); 2.60 (m, 1H); 1.98 (m, 1H); 1.54 (s, 3H); 1.42 (s, 9H).

MS (ESI, m/z) : 587.1 [M+H⁺] for C28H34N4O8S; t_R = 0.77 min.

Example 60: (2/?)-4-(6-((5/?5)-5-cyclobutyl-6-hydroxyhexa-l,3-diyn-l-yl)-3-oxo1//-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-V-hydroxy-2-methyl20 2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.1 g; 0.23 mmol) and the compound of Preparation AW (0.136 g; 0.43 mmol), and proceeding successively in analogy to Example 12, step 12.i (56% yield), Example 15, step 15.ii (79% yield) and Procedure D (37% yield), the title compound was obtained, after precipitation from water and drying, as 25 a yellowish solid (0.018 g).

Ή NMR (ί/6-DMSO) δ: 10.9 (br. s, lH);9.19(br. s, 1H); 7.56 (s, 1H); 6.27 (d, J = 1.1 Hz, 1H); 4.89 (t, J = 5.6 Hz, 1H); 4.44 (s, 2H); 3.49 (m, 1H); 3.36-3.43 (m, 2H); 3.06 (s, 3H);

2.55-2.69 (m, 4H); 1.91-2.05 (m, 3H); 1.72-1.90 (m, 4H); 1.53 (m, 3H).

MS (ESI, m/z): 462.92 [M+H⁺] for C22H27N3O6S; t_R = 0.73 min.

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Example 61: (/?)-7V-hydroxy-4-(6-(((l/?,25)-2-(hydroxymethyl)2-methylcyclopropyl)buta-l,3-diyn-l-yl)-3-oxo-lZ/-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.1 g; 0.23 mmol) and the compound of

Preparation AX (0.071 g; 0.3 mmol), and proceeding successively in analogy to

Example 12, step 12.i (70% yield) and Procedure D (36 % yield), the title compound was obtained, after precipitation from water and drying, as a beige solid (0.025g).

Ή NMR (ί/6-DMSO) 5: 10.9 (br. s, IH); 9.18 (br. s, IH); 7.53 (s, IH); 6.25 (d, J= 1.1 Hz,

IH); 4.74 (t, J = 5.8 Hz, IH); 4.43 (s, 2H); 3.48 (m, IH); 3.39 (m, IH); 3.29 (dd,

J = 5.9, 11.2 Hz, IH); 3.21 (dd, J = 5.6, 11.2 Hz, IH); 3.06 (s, 3H); 2.59 (m, IH); 1.96 (m,

IH); 1.54 (overlaid m, IH); 1.53 (br. s, 3H); 1.17 (s, 3H); 1.03 (m, IH); 0.61 (m, IH).

MS (ESI, m/z): 448.00 [M+H⁺] for C21H25N3O6S; t_R = 0.68 min.

Example 62: (/?)-7V-hydroxy-4-(6-((l-(2-hydroxyacetyl)azetidin-3-yl)buta-l,3-diyn1-yl)-3-oxo-l//-pyrrolo| 1,2-c] imidazol-2(3//)-yl)-2-methyl15 2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.1 g; 0.23 mmol) and the compound of Preparation AY (0.067 g; 0.3 mmol), and proceeding in analogy to Example 12, step 12.i (32% yield) and Procedure D (43% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a yellow solid (0.015 g).

Ή NMR (ί/6-DMSO) 5: 10.9 (m, IH); 9.19 (m, IH); 7.60 (m, IH); 6.29 (m, IH); 5.01 (m,

IH); 4.41-4.45 (m, 3H); 4.14-4.21 (m, 2H); 3.89-3.94 (m, 2H); 3.83 (m, IH); 3.73 (m, IH);

3.50 (m, IH); 3.40 (m, IH); 3.06 (s, 3H); 2.59 (m, IH); 1.97 (m, IH); 1.52 (s, 3H). MS (ESI, m/z): 476.97 [M+H⁺] for C21H24N4O7S; t_R = 0.57 min.

Example 63: (/?)-7V-hydroxy-4-(6-(5-(3-hydroxyoxetan-3-yl)penta-l,3-diyn-l-yl)25 3-oxo-lZ7-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.1 g; 0.23 mmol) and the compound of Preparation AZ (0.073 g; 0.3 mmol), and proceeding in analogy to Example 12, step 12.i (54% yield) and Procedure D (25% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a yellow solid (0.017 g).

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Ή NMR (ί/6-DMSO) δ: 7.57 (s, 1H); 6.27 (d, J = 0.9 Hz, 1H); 6.06 (m, 1H); 4.39-4.46 (m, 6H); 3.48 (m, 1H); 3.38 (overlapped m, 1H); 3.06 (s, 3H); 2.83 (s, 2H); 2.59 (m, 1H);

1.95 (m, 1H); 1.52 (m, 3H).

MS (ESI, m/z): 449.97 [M+H⁺] for C20H23N3O7S; t_R = 0.60 min.

Example 64: (/?)-7V-hydroxy-4-(6-((4-hydroxytetrahydro-2Z/-pyran-4-yl)buta- l,3-diyn-l-yl)-3-oxo-lZ/-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)-2-methyl2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.1 g; 0.23 mmol) and the compound of Preparation BA (0.077 g; 0.3 mmol), and proceeding in analogy to Example 12, step 12.i 10 (66% yield) and Procedure D (60% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a yellow solid (0.035 g).

Ή NMR (ί/6-DMSO) 5: 7.61 (d, J = 0.6 Hz, 1H); 6.29 (d, J = 1.2 Hz, 1H); 5.93 (m, 1H);

4.44 (s, 2H); 3.71-3.80 (m, 2H); 3.45-3.54 (m, 3H); 3.38 (overlapped m, 1H); 3.07 (s, 3H);

2.59 (m, 1H); 1.98 (m, 1H); 1.79-1.87 (m, 2H); 1.63-1.71 (m, 2H); 1.53 (s, 3H).

MS (ESI, m/z): 463.97 [M+H⁺] for C21H25N3O7S; t_R = 0.62 min.

Example 65: (/?)-4-(6-(((25,5/?)-5-aminotetrahydro-2Z/-pyran-2-yl)buta-l,3-diyn-

1- yl)-3-oxo-lZ7-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)-A-hydroxy-2-methyl-

2- (methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.1 g; 0.23 mmol) and the compound of 20 Preparation BB (0.074 g; 0.3 mmol), and proceeding in analogy to Example 12, step 12.i (37% yield) and Procedure D (71% yield), the title compound was obtained, after purification by prep-HPLC (Method 3), as a yellow solid (0.029 g).

Ή NMR (ί/6-DMSO) 5: 7.62 (s, 1H); 6.29 (d, J= 1.2 Hz, 1H); 4.44 (br. s, 2H); 4.27 (m, 1H); 4.11 (br.s, 1H); 3.77 (m, 1H); 3.49 (m, 1H); 3.34-3.42 (overlapped m, 2H);

3.17 (br. s, 2H); 3.06 (s, 3H); 2.98 (m, 1H); 2.56-2.67 (m, 2H); 1.85-1.99 (m, 2H); 1.59 (m,

1H); 1.51 (s, 3H); 1.26 (m, 1H).

MS (ESI, m/z): 504.01 [M+H⁺] for C21H26N4O6S; t_R= 0.51 min.

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Examples 66 and 67: (R)-4-(6-(((7R,2R)-l-fluoro2-(hydroxymethyl)cyclopropyl)buta-l,3-diyn-l-yl)-3-oxo-lZ/-pyrrolo[l,2-c]imidazol2(3Z/)-yl)-/V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide AND (R)-4-(6-(((15,25)-l-fluoro-2-(hydroxymethyl)cyclopropyl)buta-l,3-diyn-l-yl)-3-oxo5 lH-pyrrolo[l,2-c]imidazol-2(3//)-yl)-V-hydroxy-2-methyl-

2- (methylsulfonyl)butanamide:

66/67.i. (R)-4-(6-(((lR*,2R*)-l-fluoro-2-(hydroxymethyl)cyclopropyl)buta-l,3-diyn-l-yl)-

3- oxo-lH-pyrrolo[l,2-c]imidazol-2(3H)-yl)-N-hydroxy-2-methyl-

2- (methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.1 g; 0.23 mmol) and the compound of Preparation AU (0.132 g; 0.3 mmol), and proceeding in analogy to Example 12, step 12.i (65% yield), Example 15, step 15.ii (69% yield) and Procedure D (70% yield), the title compound was obtained, after precipitation from water and drying, as a beige solid (0.034 g).

Ή NMR (ί/6-DMSO) 5: 11.09 (br. s, 1H); 9.19 (br. s, 1H); 7.67 (s, 1H); 6.31 (s, 1H); 4.86-4.93 (m, 1H); 4.45 (s, 2H); 3.62-3.75 (m, 1H); 3.46-3.56 (m, 1H); 3.35-3.44 (m, 2H); 3.06 (m, 3H); 2.56-2.66 (overlapped m, 1H); 1.93-2.04 (m, 1H); 1.59-1.72 (m, 1H);

1.53 (s, 3H); 1.35-1.45 (m, 1H); 1.21-1.31 (m, 1H).

MS (ESI, m/z): 452.00 [M+H⁺] for C20H22N3O6FS; t_R = 0.67 min.

66/67. ii. (R)-4-(6-(((1R,2R)-l-fluoro-2-(hydroxymethyl)cyclopropyl)buta-l,3-diyn-l-yl)-

3- oxo-lH-pyrrolo[l,2-c]imidazol-2(3H)-yl)-N-hydroxy-2-methyl-

2-(methylsulfonyl)butanamide AND (R)-4-(6-(((lS,2S)-l-fluoro2-(hydroxymethyl)cyclopropyl)buta-l,3-diyn-l-yl)-3-oxo-lH-pyrrolo[l,2-c]imidazol2(3H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide:

Intermediate 66/67.1 (0.029 g) was separated by semi-preparative chiral HPLC Method A (EtOH-MeCN (containing 0.1% TFA) 4-1; flow rate: 20 mL/min, UV detection at 213 nm); the respective retention times of the enantiomers (flow rate: 0.8 mL/min) were 5.5 and 9.7 min. The title enantiomers, first-eluting enantiomer (0.009 g) and secondeluting enantiomer (0.01 g) respectively, were obtained as beige solids. The respective absolute configurations of the two diastereomeric compounds have not been determined.

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Example 66 and Example 67 refer to the first-eluting enantiomer and the second-eluting enantiomer respectively.

First-eluting enantiomer:

MS (ESI, m/z): 452.00 [M+H⁺] for C20H22N3O6FS; t_R = 0.67 min.

Second-eluting enantiomer:

MS (ESI, m/z): 452.00 [M+H⁺] for C20H22N3O6FS; t_R = 0.67 min.

Example 68: (7?)-4-(6-((5-(l-ammocyclopropyl)thiophen-2-yl)ethynyl)-3-oxo1//-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-V-hydroxy-2-methyl2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation E (0.11 g; 0.21 mmol) and the compound of Preparation BC (0.039 g; 0.24 mmol), and proceeding successively in analogy to Procedure F (42% yield) and Procedure I (27% yield), the title compound was obtained, after purification by prep-HPLC (Method 3), as a yellowish solid (0.007 g).

Ή NMR (ί/6-DMSO) 5: 10.94 (br. s, 1H); 9.12 (br. s, 1H); 7.45 (s, 1H); 7.10 (d,

J = 3.7 Hz, 1H); 6.68 (d, J = 3.7 Hz, 1H); 6.25 (d, J = 0.7 Hz, 1H); 4.45 (s, 2H); 3.49 (m, 1H); 3.39 (m, 1H); 3.06 (s, 3H); 2.59 (m, 1H); 1.97 (m, 1H); 1.52 (s, 3H); 1.05-1.10 (m, 2H); 0.94-0.99 (m, 2H).

MS (ESI, m/z): 518.00 [M+H⁺] for C21H24N4O5S2; t_R = 0.55 min.

Example 69: (/?)-4-(6-((4-(3-aminooxetan-3-yl)phenyl)ethynyl)-3-oxo20 1//-pyrrolo[ 1,2-c] imidazol-2(3//)-yl)-V-hydroxy-2-methyl2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.12 g; 0.28 mmol) and the compound of Preparation BD (0.115 g; 0.37 mmol) and proceeding successively in analogy to Procedure E (63% yield) and Procedure I (77% yield), the title compound was obtained, 25 after purification by prep-HPLC (Method 3), as a brownish solid (0.02 g).

Ή NMR (i/₆-DMSO) 5: 10.96 (s, 1H); 9.19 (br. s, 1H); 7.61-7.64 (m, 2H); 7.49-7.52 (m, 2H); 7.47 (d, J = 0.7 Hz, 1H); 6.28 (d, J = 1.2 Hz, 1H); 4.64-4.70 (m, 4H); 4.47 (s, 2H);

3.51 (m, 1H); 3.41 (m, 1H); 3.08 (s, 3H); 2.62 (m, 2H); 1.99 (m, 1H); 1.54 (s, 3H).

MS (ESI, m/z): 487.24 [M+H⁺] for C23H26N4O6S; t_R = 0.42 min.

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Example 70: (/?)-N-hydroxy-4-(6-((4-(3-(hydroxymethyl)oxetan-

3-yl)phenyl)ethynyl)-3-oxo-l//-pyrrolo|l,2-c]imidazol-2(3//)-yl)-2-methyl2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.105 g; 0.25 mmol) and the compound of

Preparation BE (0.094 g; 0.32 mmol) and proceeding successively in analogy to Procedure E (60% yield) and Procedure B (15% yield), the title compound was obtained, after purification by prep-HPLC (Method 1) as an off-white solid (0.011 g).

Ή NMR (i/₆-DMSO) 5: 10.96 (s, IH); 9.19 (br. s, IH); 7.47 (s, IH); 7.45-7.47 (m, 2H); 7.15-7.20 (m, 2H); 6.28 (s, IH); 5.16 (m, IH); 4.71 (s, 4H); 4.46 (s, 2H); 3.72 (d, 10 J = 5.4 Hz, 2H); 3.51 (m, IH); 3.40 (m, IH); 3.07 (s, 3H); 2.60 (overlapped m, IH);

1.97 (m, IH); 1.53 (s, 3H).

MS (ESI, m/z): 502.00 [M+H⁺] for C24H27N3O7S; t_R = 0.64 min.

Example 71: (/?)-/V-hydroxy-4-(6-((4-(2-hydroxyacetamido)phenyl)ethynyl)-3-oxolZ/-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.12 g; 0.28 mmol) and 2-hydroxyN-(4-iodophenyl)acetamide (0.102 g; 0.37 mmol; commercial), and proceeding successively in analogy to Procedure E (57% yield) and Procedure D (31% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a white solid (0.024 g).

Ή NMR (iA-DMSO) 5: 10.96 (m, IH); 9.85 (s, IH); 9.10-9.27 (m, IH); 7.74-7.78 (m, 2H); 7.40-7.46 (m, 3H); 6.26 (d, J = 1.2 Hz, IH); 5.68 (t, J = 6.1 Hz, IH); 4.46 (s, 2H); 4.01 (d, J = 6.0 Hz, 2H); 3.51 (m, IH); 3.40 (m, IH); 3.08 (s, 3H); 2.60 (m, IH); 1.99 (m, IH);

1.54 (s, 3H).

MS (ESI, m/z): 489.01 [M+H⁺] for C22H24N4O7S; t_R = 0.62 min.

Example 72: (/?)-4-(6-((4-(l-aminocyclopropyl)phenyl)ethynyl)-3-oxo1//-pyrrolo| 1,2-c] imidazol-2(3//)-yl)-V-hydroxy-2-methyl2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.122 g; 0.28 mmol) and the compound of Preparation BF (0.11 g; 0.37 mmol), and proceeding successively in analogy to

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Example 12, step 12.i (32% yield) and Procedure B (21% yield), the title compound was obtained, after precipitation, filtration and drying, as a white solid (0.007 g).

Ή NMR (rts-DMSO) δ: 9.24 (s, 1H); 7.44 (s, 1H); 7.37-7.40 (m, 2H); 7.29-7.33 (m, 2H);

6.26 (d, J= 1.1 Hz, 1H); 4.46 (s, 2H); 3.50 (m, 1H); 3.40 (m, 1H); 3.08 (s, 3H); 2.61 (m, 5 1H); 1.98 (m, 1H); 1.54 (s, 3H); 0.92-1.03 (m, 4H).

MS (ESI, m/z): 471.13 [M+H⁺] for C23H26N4O5S; t_R = 0.56 min.

Example 73: (/?)-/V-hydroxy-4-(6-(5-((ls,3^)-l-hydroxy-

3-(hydroxymethyl)cyclobutyl)penta-l,3-diyn-l-yl)-3-oxo-lZ/-pyrrolo[l,2-c]imidazol2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.1 g; 0.23 mmol) and the compound of Preparation BG (0.082 g; 0.30 mmol), and proceeding successively in analogy to Example 12, step 12.i (32% yield) and Procedure B (21% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a yellowish solid (0.007 g).

Ή NMR (i/₆-DMSO) δ: 10.91 (br. s, 1H); 9.19 (br. s, 1H); 7.55 (s, 1H); 6.26 (d, J = 1.2 Hz,

1H); 5.21 (s, 1H); 4.48 (m, 1H); 4.43 (s, 2H); 3.48 (m, 1H); 3.32-3.40 (m, 3H); 3.06 (s,

3H); 2.61 (m, 1H); 2.02-2.09 (m, 2H); 1.90-1.99 (m, 2H); 1.68-1.75 (m, 2H); 1.54 (s, 3H). MS (ESI, m/z): 478.0 [M+H⁺] for C22H27N3O7S; t_R = 0.60 min.

Example 74: (phosphonooxy)methyl (R)-(l-((2-(4-(hydroxyamino)-3-methyl3-(methylsulfonyl)-4-oxobutyl)-3-oxo-2,3-dihydro-lZ/-pyrrolo[l,2-c]imidazol20 6-yl)buta-l,3-diyn-l-yl)cyclopropyl)carbamate:

Starting from the compound of Preparation H (0.089 g; 0.21 mmol) and the compound of Preparation BH (0.133 g; 0.28 mmol), and proceeding successively in analogy to Example 12, step 12.i (52% yield) and Procedure I (10% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a white solid (0.024 g).

'HNMR (i/₆-DMSO) δ: 10.94 (s, 1H); 9.18 (s, 1H); 8.33 (s, 1H); 7.55 (s, 1H); 6.25 (s, 1H); 5.34-5.41 (m, 2H); 4.43 (s, 2H); 3.45-3.50 (m, 1H); 3.24-3.43 (overlapped m, 1H); 3.05 (s, 3H); 2.44-2.62 (overlapped m, 1H); 1.96 (m, 1H); 1.52 (s, 3H); 1.20-1.26 (m, 2H); 1.08-1.14 (m, 2H).

MS (ESI, m/z): 573.0 [M+H⁺] for C21H25N4O11PS; t_R = 0.53 min.

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Example 75: (R)-(l-((2-(4-(hydroxyammo)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-

3- oxo-2,3-dihydro-lH-pyrrolo[l,2-c]imidazol-6-yl)buta-l,3-diynl-yl)cyclopropyl)methyl ((phosphonooxy)methyl) carbonate:

75.i. Chloromethyl ((l-((2-((3R)-3-methyl-3-(methylsulfonyl)-4-oxo-4-(((tetrahydro-

2H-pyran-2-yl)oxy)amino)butyl)-3-oxo-2,3-dihydro-lH-pyrrolo[1,2-c] imidazol-6-yl)buta-

1,3-diyn-l-yl)cyclopropyl)methyl) carbonate:

To a solution of intermediate 15.i (0.14 g; 0.27 mmol) in DCM (5 mL), cooled at 0°C, were added Pyr (0.044 mL; 0.54 mmol) and chloromethyl chloroformate (0.03 mL;

0.33 mmol). The reaction mixture was stirred at 0°C for 1.75 h. Sat. aq. NaHCCh (10 mL) 10 was added and the mixture was extracted with DCM (10 mL). The org. layer was washed with brine (10 mL), dried over MgSCfi, filtered and evaporated under reduced pressure.

The reaction mixture was purified by CC (Hept-EA) to afford the title compound as a yellow gum (0.041 g; 25% yield).

MS (ESI, m/z): 610.0 [M+H⁺] for C27H32N3O9CIS; t_R = 0.90 min.

75. ii. ((Di-tert-butoxyphosphoryl)oxy)methyl ((l-((2-((3R)-3-methyl-3-(methylsulfonyl)-

4- oxo-4-(((tetrahydro-2H-pyran-2-yl)oxy)amino)butyl)-3-oxo-2,3-dihydro- lH-pyrrolo[1,2-c]imidazol-6-yl)buta-l, 3-diyn-l-yl)cyclopropyl)methyl) carbonate:

To a solution of intermediate 75.i (0.041 g; 0.067 mmol) in DME (1 mL) was added tetra-n-butylammonium di-ieri-butylphosphate (0.042 g; 0.094 mmol). The reaction 20 mixture was heated at 80°C for 4 h. Water (5 mL) was added and the mixture was extracted with EA (10 mL). The aq. layer was extracted with EA (5 mL). The combined org. layers were washed with brine (5 mL), dried over MgSCU and concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a yellow solid (0.024 g: 46% yield).

'H NMR (ί/6-DMSO) δ (mixture of diastereomers): 11.36 (s, 0.5H); 11.31 (s, 0.5H); 7.53 (s, 0.5H); 7.52 (s, 0.5H); 6.23 (s, 1H); 5.54 (s, 1H); 5.51 (s, 1H); 4.84 (m, 0.5H);

4.46 (m, 0.5H); 4.36-4.44 (m, 2H); 4.12 (s, 2H); 4.03 (m, 0.5H); 3.95 (m, 0.5H);

3.45-3.52 (m, 1H); 3.37-3.43 (m, 2H); 3.05 (s, 1.5H); 3.03 (s, 1.5H); 2.57 (m, 1H);

1.95 (m, 1H); 1.60-1.66 (m, 2H); 1.55 (s, 1.5H); 1.54 (s, 1.5H); 1.47-1.49 (m, 4H); 1.42 (s, 30 18H); 1.05-1.12 (m,4H).

MS (ESI, m/z): 784.0 [M+H⁺] for C35H50N3O13PS; t_R = 0.94 min.

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75.iii. (R)-(l-((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-3-oxo-

2,3-dihydro-lH-pyrrolo[1,2-c]imidazol-6-yl)buta-l, 3-diyn-l-yl)cyclopropyl)methyl ((phosphonooxy)methyl) carbonate:

Starting from the intermediate 75.ii (0.02 g; 0.025 mmol) and proceeding in analogy to 5 Procedure I, the title compound was obtained, after purification by prep-HPLC (Method 1), as a white solid (0.024 g; 28% yield).

Ή NMR (rtd-DMSO) 5: 10.94 (s, IH); 9.18 (m, IH); 7.55 (s, IH); 6.25 (s, IH); 5.45 (d, J = 13.2 Hz, 2H); 4.42 (s, 2H); 4.09 (s, 2H); 3.48 (m, IH); 3.37 (m, IH); 3.05 (s, 3H);

2.46-2.62 (overlapped m, IH); 1.96 (m, IH); 1.52 (s, 3H); 1.08 (d, J = 3.8 Hz, 4H).

MS (ESI, m/z): 588.0 [M+H⁺] for C22H26N3O12PS; t_R = 0.59 min.

Example 76: (/?)-V-hydroxy-4-(6-((2-(2-hydroxypropan-2-yl)thiazol-5-yl)ethynyl)3-oxo-lZ7-pyrrolo[l,2-c]imidazol-2(3Z/)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation E (0.113 g; 0.21 mmol) and the compound of Preparation BI (0.073 g; 0.43 mmol), and proceeding successively in analogy to 15 Procedure F (73% yield) and Procedure B (64% yield), the title compound was obtained, after purification by CC (EA-MeOH), as a white solid (0.049 g).

Ή NMR (ί/6-DMSO) 5: 10.95 (s, IH); 9.18 (s, IH); 7.88 (s, IH); 7.52 (d, J = 0.6 Hz, IH); 6.29 (m, IH); 6.14 (s, IH); 4.46 (s, 2H); 3.49 (m, IH); 3.39 (m, IH); 3.07 (s, 3H); 2.60 (m, IH); 1.97 (m, IH); 1.53 (s, 3H); 1.50 (s, 6H).

MS (ESI, m/z): 481.01 [M+H⁺] for C20H24N4O6S2; t_R = 0.65 min.

Example 77: (/?)-4-(6-((4-((4-ammopiperidm-l-yl)methyl)phenyl)ethynyl)-3-oxo1//-pyrrolo[ 1,2-c] imidazol-2(3//)-yl)-V-hydroxy-2-methyl2-(methylsulfonyl)butanamide dihydrochloride:

Starting from the compound of Preparation H (0.2 g; 0.472 mmol) and ieri-butyl 25 (l-(4-iodobenzyl)piperidin-4-yl)carbamate (0.102 g; 0.37 mmol; prepared as described in

WO 2013/092674), and proceeding successively in analogy to Procedure E (71% yield) and Procedure I (37% yield), the title compound was obtained, after purification by prep-HPLC (Method 3), as a white solid (0.014 g).

Ή NMR (rt6-DMSO) 5: 7.45 (s, IH); 7.44 (d, J = 8.2 Hz, 2H); 7.30 (d, J = 8.2 Hz, 2H); 30 6.26 (d, J = 1.2 Hz, IH); 4.46 (s, 2H); 3.47-3.53 (m, IH); 3.45 (s, 2H); 3.37-3.41 (m, IH);

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3.07 (s, 3H); 2.73 (m, 2H); 2.64-2.66 (m, 1H); 2.58 (m, 1H); 1.93-1.98 (m, 3H); 1.72 (m, 2H); 1.50 (s, 3H); 1.29-1.35 (m, 2H).

MS (ESI, m/z): 528.11 [M+H⁺] for C26H33N5O5S; t_R = 0.49 min.

Examples 78 and 79: (7?)-4-(6-(((77?,27?)-2-fluoro5 2-(hydroxymethyl)cyclopropyl)buta-l,3-diyn-l-yl)-3-oxo-EH-pyrrolo[l,2-c]imidazol2(3ZZ)-yl)-/V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide AND (R)-4-(6-(((75,25)-2-fluoro-2-(hydroxymethyl)cyclopropyl)buta-l,3-diyn-l-yl)-3-oxol/Z-pyrrolo[l,2-c]imidazol-2(3ZZ)-yl)-A-hydroxy-2-methyl2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.15 g; 0.354 mmol) and either the first-eluting enantiomer (1^st variant) or the second-eluting enantiomer (2^nd variant) of Preparation BJ (each time 0.116 g (0.39 mmol)), and proceeding in analogy to Example 12, step 12.i (1^st variant: 76% yield; 2^nd variant: 84% yield) and Procedure D (1^st variant: 85% yield; 2^nd variant: 85% yield), the title compounds were obtained, after purification by CC (DCM-MeOH), in the 1^st variant case, as a yellow solid (0.103 g), and, in the 2^nd variant case, as a yellow solid (0.115 g).

1^st variant product:

Ή NMR (z/6-DMSO) 5: 10.94 (s, 1H); 9.18 (s, 1H); 7.56 (d, J = 0.9 Hz, 1H); 6.25 (d, J = 1.2 Hz, 1H); 5.23 (t, J = 6.1 Hz, 1H); 4.42 (s, 2H); 3.59-3.71 (m, 2H); 3.49 (m, 1H);

3.38 (m, 1H); 3.06 (s, 3H); 2.59 (m, 1H); 1.90-1.97 (m, 2H); 1.52 (s, 3H); 1.31-1.36 (m,

2H).

MS (ESI, m/z): 451.99 [M+H⁺] for C20H22N3O6FS; t_R = 0.67 min.

2^nd variant product:

Ή NMR (z/6-DMSO) 5: 10.94 (s, 1 H); 9.18 (s, 1H); 7.57 (d, J = 0.9 Hz, 1H); 6.26 (d,

J = 1.2 Hz, 1H); 5.23 (t, J = 6.1 Hz, 1H); 4.43 (s, 2H); 3.58-3.71 (m, 2H); 3.48 (m, 1H);

3.39 (m, 1H); 3.06 (s, 3H); 2.59 (m, 1H); 1.91-1.98 (m, 2H); 1.53 (s, 3H); 1.32-1.37 (m, 2H).

MS (ESI, m/z): 452.03 [M+H⁺] for C20H22N3O6FS; t_R = 0.65 min.

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Example 80: (/?)-/V-hydroxy-4-(6-((4-((4-hydroxypiperidm-

1- yl)methyl)phenyl)ethynyl)-3-oxo-lZZ-pyrrolo[l,2-c]imidazol-2(3ZZ)-yl)-2-methyl-

2- (methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.2 g; 0.47 mmol) and 5 l-(4-iodobenzyl)piperidin-4-ol (0.165 g; 0.52 mmol; commercial), and proceeding successively in analogy to Procedure E (89% yield) and Procedure I (35% yield), the title compound was obtained, after purification by prep-HPLC (Method 3), as a beige solid (0.047 g).

MS (ESI, m/z): 529.1 [M+H⁺] for C26H32N4O6S; t_R = 0.54 min.

Example 81: (7?)-4-(6-((4-(4-aminopiperidm-l-yl)phenyl)ethynyl)-3-oxolZZ-pyrrolo[l,2-c]imidazol-2(3ZZ)-yl)-/V-hydroxy-2-methyl2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.113 g; 0.26 mmol) and l-(4-iodophenyl)piperidin-4-amine trifluoroacetate (0.118 g; 0.28 mmol), and proceeding 15 successively in analogy to Procedure E (100% yield) and Procedure I (41% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a beige solid (0.051 g).

MS (ESI, m/z): 514.10 [M+H⁺] for C25H31N5O5S; t_R = 0.56 min.

Example 82: (R)-V-hydroxy-2-methyl20 4-(6-((4-(methylsulfonamidomethyl)phenyl)ethynyl)-3-oxo-lZZ-pyrrolo[l,2-c]imidazol2(3//)-yl)-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation H (0.2 g; 0.47 mmol) and 7V-(4-iodobenzyl)methanesulfonamide (0.237 g; 0.71 mmol), and proceeding successively in analogy to Procedure E (70% yield), and Procedure D (81% yield), the title compound 25 was obtained as a greyish solid (0.11 g).

Ή NMR (rt6-DMSO) 5: 10.96 (s, 1H); 9.19 (s, 1H); 7.62 (t, J = 6.4 Hz, 1H);

7.46-7.50 (overlapped m, 2H); 7.47 (s, 1H); 7.38 (d, J = 8.2 Hz, 2H); 6.28 (m, 1H); 4.47 (s, 2H); 4.18 (d, J = 6.3 Hz, 2H); 3.50 (m, 1H); 3.41 (m, 1H); 3.08 (s, 3H); 2.88 (s, 3H);

2.60 (m, 1H); 1.99 (m, 1H); 1.54 (s, 3H).

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2015226250 05 Nov 2018

MS (ESI, m/z): 523.0 [M+H⁺] for C22H26N4O7S2; t_R = 0.67 min.

Example 83: (/?)-V-hydroxy-2-methyl-2-(methylsulfonyl)-4-(6-((l-(oxetan3-yl)azetidin-3-yl)buta-l,3-diyn-l-yl)-3-oxo-lZ/-pyrrolo[l,2-c]imidazol2(3Z/)-yl)butanamide:

83. i. 4-iodo-lH-pyrrole-2-carbaldehyde oxime:

To a solution of NH2OH.HCI (17.61 g, 253.42 mmol) in MeOH (600 mL) was added NaOAc.3H2O (35.1 g; 257.94 mmol) and the mixture is stirred at rt for 5 min. 4-iodo17/-pyrrole-2-carbaldehyde (50.00 g; 226.25 mmol) was added portion-wise and the reaction mixture was stirred for 1 h. The mixture was evaporated under reduced pressure to 10 dryness, the residue was dissolved in EA, washed with water (5 x 100 mL), filtered and dried over Na2SO4. The solvent was evaporated to give the title compound as a white solid (53 g; 99% yield).

Ή NMR (r/6-DMSO) 5: 11.42-11.53 (br. s, IH); 10.80 [major] and 11.34 (both s, total IH); 7.24 and 7.89 [major] (both s, IH); 6.93 [major] and 7.00 (both dd, 15 J = 1.5, 2.7 Hz, total IH); 6.40 [major] and 6.73 (both t, J = 1.8 Hz, total IH).

83. ii. (4-iodo-lH-pyrrol-2-yl)methanamine:

To a solution of intermediate 83.i (10.0 g; 42.37 mmol) in AcOH (250 mL) under argon was added a first portion (approximately 2/3) of Zn powder (total amount: 16.62 g (254.24 mmol)) and the mixture was stirred for 20 min. Then the remaining portion of Zn 20 powder was added and stirring was continued for an additional 15 min. The solids were filtered off and the filtrate was evaporated under reduced pressure (bath temperature below 40°C). The residue was dissolved in EA (200 mL), washed with 5-7% aq. NaOH (50 mL) and brine (50 mL), and dried over anhydrous MgSO4. After filtration and evaporation to dryness, the title compound was obtained as a brown solid (7.7 g; 81.7% yield).

Ή NMR (r/6-DMSO) 5: 10.89 (br. s, IH); 6.74 (d, J = 1.5 Hz, IH); 5.93 (m, IH); 3.58 (s, 2H).

83. Hi. 6-iodo-lH-pyrrolo[1,2-c]imidazol-3(2H)-one:

To a solution of CDI (4.69 g; 28.92 mmol) in THF (150 mL), cooled with an ice-water bath, was added dropwise a solution of intermediate 83.ii (6.112 g; 27.53 mmol) in THF

- 163 2015226250 05 Nov 2018 (20 mL). Immediately after addition completed, NaH (2.36 g; 60% in mineral oil; 59.0 mmol) was added and the mixture is stirred for 4 h. Then, water (2 mL) was added and the solvent was evaporated under reduced pressure. The residue was purified by CC (DCM-EA) to give the title compound as a pale yellow solid (3.35 g; 49% yield).

^!H NMR (ί/6-DMSO) δ: 8.55 (br. s, 1H); 7.27 (d, J = 1.6 Hz, 1H); 6.17 (d, J = 1.6 Hz, 1H); 4.34 (s, 2H).

MS (ESI, m/z): 248.9 [M+H⁺] for C₆H₅N₂OI; t_R = 0.66 min.

83. iv. Ethyl 4-(6-iodo-3-oxo-lH-pyrrolo[1,2-c]imidazol-2(3H)-yl)-2-methyl2-(methylsulfonyl)butanoate:

To a solution of intermediate 83.iii (1.55 g; 6.25 mmol) in DME (30 mL) was added NaH (0.275 g; 60% in mineral oil; 6.88 mmol). The mixture was stirred at rt for 1.5 h. (R)-ethyl

4-bromo-2-methyl-2-(methylsulfonyl)butanoate (1.88 g; 6.5 mmol) was added. The reaction proceeded at rt for 2 h. Aq. NH4CI (2 mL) was added and the solvent was removed under reduced pressure. The residue was dissolved in EA (150 mL), washed with water (50 mL) and brine (50 mL), and dried over Na2SO4. After filtration and evaporation to dryness, the residue was purified by CC (PE-EA) to afford the title compound as a pale yellow semi-solid (1.58 g, 55% yield).

Ή NMR (ί/6-DMSO) 5: 7.32 (d, J =1.0 Hz, 1H); 6.24 (m, 1H); 3.89-4.00 (m, 2H);

3.60 (m, 1H); 3.47 (m, 1H); 3.13 (s, 3H); 2.61 (m, 1H); 2.06 (m, 1H); 1.57 (s, 3H); 1.12 (t, 20 J = 7.1 Hz, 3H).

MS (ESI, m/z): 455.00 [M+H⁺] for C14H19N2O5IS; t_R = 0.82 min.

83. v. Ethyl 4-(6-ethynyl-3-oxo-lH-pyrrolo[l,2-c]imidazol-2(3H)-yl)-2-methyl2-(methylsulfonyl)butanoate:

Starting from intermediate 83.iv (2 g; 4.4 mmol) and proceeding in analogy to Procedure C (quant.) and Preparation H, step H.ii (83% yield), the title compound was obtained, after purification by CC (Hept-EA), as a beige foam (1.28 g).

Ή NMR (ί/6-DMSO) 5: 7.41 (s, 1H); 6.20 (d, J = 1.2 Hz, 1H); 4.36 (s, 2H); 3.99 (s, 1H);

3.89-3.98 (m, 2H); 3.62 (m, 1H); 3.47 (m, 1H); 3.12 (s, 3H); 2.61 (m, 1H); 2.06 (m, 1H);

1.57 (s, 3H); 1.11 (t, J = 7.1 Hz, 3H).

MS (ESI, m/z): 352.93 [M+H⁺] for C16H20N2O5S; t_R = 0.77 min.

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83. vi. Ethyl 4-(6-(azetidin-3-ylbuta-l,3-diyn-l-yl)-3-oxo-lH-pyrrolo[l,2-c]imidazol2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanoate:

Starting from the intermediate 83,v (0.48 g; 1.36 mmol) and intermediate AY.ii (0.375 g;

1.9 mmol) and proceeding in analogy to Example 12, step 12.i, the title compound was 5 obtained, after purification by CC (DCM-MeOH), as a beige foam (0.257 g; 44% yield).

Ή NMR (ί/6-DMSO) 5: 7.61 (s, IH); 6.28 (d, J = 1.1 Hz, IH); 4.38 (s, 2H); 4.05-4.15 (m, 2H); 3.90-3.99 (m, 3H); 3.58-3.66 (m, 2H); 3.44-3.51 (m, 2H); 3.12 (s, 3H); 2.60 (m, IH); 2.07 (m, IH); 1.57 (s, 3H); 1.11 (t, J = 7.1 Hz, 3H).

MS (ESI, m/z): 432.2 [M+H⁺] for C21H25N3O5S; t_R = 0.62 min.

83.vii. Ethyl 2-methyl-2-(methylsulfonyl)-4-(6-((l-(oxetan-3-yl)azetidin-3-yl)buta- l,3-diyn-l-yl)-3-oxo-lH-pyrrolo[l,2-c]imidazol-2(3H)-yl)butanoate:

To a solution of intermediate 83.vi (0.237 g; 0.549 mmol) in DCM (7.2 mL) were added oxetan-3-one (0.119 g; 1.65 mmol) and NaBH(OAc)3 (0.706 g; 3.33 mmol). The reaction mixture was stirred at rt for 2 h. Sat. aq. NaHCO3 (10 mL) and DCM (10 mL) were added.

The aq. layer was extracted 3 times with DCM-MeOH (9-1, 3 x 10 mL). The combined org. layers were dried over MgSO4, filtered and concentrated down. The residue was purified by CC (DCM-MeOH) to afford the title compound as an orange oil (0.272 g).

Ή NMR (ί/6-DMSO) 5: 7.59 (d, J= 1.2 Hz, IH); 6.27 (d, J= 1.2 Hz, IH); 4.51-4.54 (m, 2H); 4.45 (m, IH); 4.37 (s, 2H); 4.31 (m, 3H); 3.90-3.99 (m, 2H); 3.41-3.69 (m, 6H);

3.12 (s,3H); 2.56-2.65 (m, IH); 2.02-2.11 (m, IH); 1.57 (s, 3H); 1.11 (t, J = 7.1 Hz, 3H).

MS (ESI, m/z): 488.0 [M+H⁺] for C24H29N3O6S; t_R = 0.60 min.

83.viii. (R)-2-methyl-2-(methylsulfonyl)-4-(6-((l-(oxetan-3-yl)azetidin-3-yl)buta-l,3-diynl-yl)-3-oxo-lE[-pyrrolo[l,2-c]imidazol-2(3E[)-yl)butanoic acid lithium salt:

To an ice-chilled solution of intermediate 83.vii (0.140 g; 0.288 mmol) in a 25 THE-MeOH-H2O mixture (2-2-1; 0.75 mL) was added lithium hydroxide (0.0277 g;

0.37 mmol). The reaction mixture was warmed to rt (about 15 min) and stirred at rt for 1 h. The compound was concentrated to dryness to afford the title salt as an orange gum (0.134 g; quant.).

MS (ESI, m/z): 460.0 [M+H⁺] for C22H25N3O6S; t_R = 0.53 min.

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83.ix. (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-4-(6-((l-(oxetan-3-yl)azetidin-3-yl)buta- l,3-diyn-l-yl)-3-oxo-lH-pyrrolo[l,2-c]imidazol-2(3H)-yl)butanamide:

Starting from intermediate 83.viii (0.134 g; 0.288 mmol) and proceeding in analogy to Preparation C, step C.iv (67% yield) and Procedure I (12% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a white solid (0.001 g).

‘HNMR (rL-DMSO) 5: 9.06-9.14 (br. s, IH); 7.56 (d, J= 1.2 Hz, IH); 6.26 (d, J= 1.2 Hz, IH); 4.53 (t, J = 6.6 Hz, 2H); 4.43 (s, 2H); 4.31 (dd, J = 5.3, 6.4 Hz, 2H); 3.67 (m, IH);

3.52 (overlapped t, J = 7.6 Hz, 2H); 3.30-3.49 (overlapped m, 3H); 3.10-3.13 (m, 2H); 3.05 (s, 3H); 2.58 (m, IH); 1.95 (m, IH); 1.51 (s, 3H).

MS (ESI, m/z): 475.08 [M+H⁺] for C22H26N4O6S; t_R = 0.51 min.

The racemic mixtures of Reference Examples 1 to 10 can be separated into their enantiomers using, for example, chiral HPLC. Thus the following further disclosure compounds or salts would be obtained:

- (R)-7V-hydroxy-4-(6-(4-(3-hydroxyoxetan-3-yl)phenyl)-3-oxo-1 //-pyrrol0[ 1,2-c]imidazol15 2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (R)-4-(6-((4-(2-ethoxypropan-2-yl)phenyl)ethynyl)-3-oxo-l/7-pyrrolo[l,2-c]imidazol2(3//)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (R)-4-(6-((2-fluoro-4-(hydroxymethyl)phenyl)ethynyl)-3-oxo-l/7-pyrrolo[l,2-c]imidazol2(3//)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (R)-7V-hydroxy-4-(6-(4-(3-hydroxy-3-methylbut-l-yn-l-yl)phenyl)-3-oxoI//-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfbnyl)butanamide;

- (R)-7V-hydroxy-4-(6-(5-hydroxy-5-methylhexa-1,3-diyn-l-yl)-3-oxo-

I//-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfbnyl)butanamide;

- (R)-7V-hydroxy-2-methyl-4-(6-((4-((4-methylpiperazin-1 -yl)methyl)phenyl)ethynyl)-

3-oxo- 17/-pyrrolo[l,2-c]imidazol-2(3//)-yl)-2-(methylsulfonyl)butanamide;

- (R)-7V-hydroxy-4-(6-(4-(2-hydroxyethoxy)phenyl)-3-oxo-l//-pyrrolo[l,2-c]imidazol2(3//)-yl)-2-methyl-2-(methylsulfbnyl)butanamide;

- (R)-7V-hydroxy-4-(6-(4-(2-methoxyethoxy)phenyl)-3-oxo- I //-pyrrolo[ 1,2-c]imidazol2(3//)-yl)-2-methyl-2-(methylsulfbnyl)butanamide.

- (R)-4-(6-(2-fluoro-4-methylphenyl)-3-oxo-177-pyrrolo[l,2-c]imidazol-2(3//)-yl)N-hydroxy-2 -methy 1-2 -(methylsulfonyl)butanamide; and

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- (R)-4-(6-(3-fluoro-4-isopropoxyphenyl)-3-oxo-l//-pyrrolo[l,2-c]imidazol-2(3//)-yl),V- hy d rox y-2 -methy 1-2 -(methylsulfonyl)butanamide.

Pharmacological properties of the invention compounds

In vitro assays

Bacterial growth minimal inhibitory concentrations:

Exiierimental methods:

Minimal Inhibitory Concentrations (MICs; mg/L) were determined in cation-adjusted Mueller-Hinton Broth by a microdilution method following the description given in “Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow 10 Aerobically”, Approved standard, 7^th ed., Clinical and Laboratory Standards Institute (CLSI) Document M7-A7, Wayne, PA, USA (2006).

Results:

All Example compounds were tested against several Gram-positive and Gram-negative bacteria. Typical antibacterial test results are given in Table 1 hereafter (MICs in mg/L). K. 15 pneumoniae A-651 is a multiply-resistant strain (in particular quinolone-resistant), while E.

coli ATCC25922 and A aeruginosa ATCC27853 are quinolone-sensitive strains.

Example No.	MIC for E. coli ATCC25922	MIC for P. aeruginosa ATCC27853	MIC for K. Pneumoniae A-651
RE1	8	16	16
RE2	2	8	2
RE3	0.5	4	1
RE4	0.25	2	0.5
RE5	2	4	8
RE6	2	2	8
RE7	4	8	8
RE8	2	8	2

2015226250 05 Nov 2018

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Example No.	MIC for	MIC for	MIC for
E. coli	P. aeruginosa	K. Pneumoniae
ATCC25922	ATCC27853	A-651
RE9	0.125	0.5	2
RE10	0.25	2	8
1	0.125	1	< 0.063
2	0.5	1	1
3	0.125	2	0.5
4	2	4	2
5	< 0.063	0.5	0.125
6	0.031	0.5	0.125
7	0.125	0.5	0.25
8	8	4	8
9	0.25	0.5	0.5
10	0.25	0.5	0.25
11	8	8	16
12	0.25	0.25	0.25
13	0.125	0.5	0.25
14	0.125	1	0.25
15	0.5	1	1
16	< 0.063	0.5	0.25
17	1	1	1
18	0.5	1	1
19	0.25	1	0.5
20	1	4	4
21	0.25	1	1
22	0.125	1	0.5
23	1	4	4
24	8	8	32
25	0.125	1	0.25
26	1	4	1
27	< 0.063	0.5	0.25
28	< 0.063	1	0.25
29	0.25	2	0.5
30	0.125	0.5	0.25
31	1	1	1
32	<0.063	0.5	0.25
33	0.5	1	0.5

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Example No.	MIC for E. coli ATCC25922	MIC for P. aeruginosa ATCC27853	MIC for K. Pneumoniae A-651
34	0.125	16	1
35	0.25	2	0.5
36	0.125	0.5	0.25
37	0.5	4	1
38	0.25	1	0.25
39	2	4	4
40	< 0.063	1	0.25
41	1	4	2
42	8	4	8
43	8	8	16
44	< 0.063	1	0.25
45	0.25	4	1
46	1	4	2
47	< 0.063	8	0.25
48	< 0.063	1	0.25
49	< 0.063	4	0.125
52	< 0.063	2	< 0.063
53	0.25	8	0.25
54	0.125	1	1
55	0.125	4	1
56	0.25	2	1
57	1	4	2
58	4	4	8
59	1	8	1
60	0.5	4	1
61	0.25	0.25	0.25
62	1	1	4
63	2	4	4
64	4	4	8
65	2	1	8
66	0.125	1	0.5
67	0.125	0.5	0.5
68	0.125	1	0.125
69	0.5	2	2
70	1	2	2

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Example No.	MIC for E. coli ATCC25922	MIC for P. aeruginosa ATCC27853	MIC for K. Pneumoniae A-651
71	0.25	1	1
72	0.125	0.5	0.25
73	8	4	16
75	1	2	2
76	1	2	2
77	8	2	16
78	0.25	0.5	0.5
79	0.25	0.5	0.25
80	1	1	2
81	8	2	16
82	0.5	1	1
83	0.5	1	0.5
Cipro	0.5	>32	>32

Table 1

The compounds of Examples 37, 50, 51 and 74 were tested against wild-type E. coli A-1261 in the absence of alkaline phosphatase or esterase, in the presence of an alkaline phosphatase and in the presence of an esterase. The corresponding antibacterial test results are given in Table 2 hereafter (MICs in mg/L).

Example No.	MIC for£. coli A-1261
In the absence of alkaline phosphatase or esterase	In the presence of an alkaline phosphatase (2 i.U./mL)	In the presence of an esterase (10 i.U./mL)
37	0.25	0.125	0.25
50	2	1	0.5
51	>16	0.5	16
74	4	0.25	4

Table 2

Claims

1. A compound of formula I

Claims

I wherein

R¹ represents the group M;

M is one of the groups M^A, M^B and M^c represented below r1A _R3A

M^A M^B

5 wherein A represents a bond, CH=CH or OC;

U represents N or CH;

V represents N or CH;

W represents N or CH;

R^1A represents H or halogen;

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R^2A represents H, (Ci-C3)alkoxy or halogen;

R^3A represents H, halogen, (Ci-C3)alkoxy, hydroxy(C2-C4)alkoxy, dihydroxy(C3-C4)alkoxy, (C1 -C3)alkoxy(C 1 -C3)alkoxy, (C1 -C3)thioalkoxy, trifluoromethoxy, trifluoromethyl, amino, hydroxyfCi-CQalkyl, 1,2-dihydroxyethyl,

5 1-hydroxy-2,2-difluoroethyl, (Ci-C3)alkoxy(Ci-C4)alkyl, 2-hydroxy-l-oxoethyl, [(C i-C'₄)alkoxy] carbonyl, methylsulfonamidomethyl, 3 -hydroxy-3-methylbut-1 -yn-1 -yl,

1 -yl, 1 -(carbamoyloxy)methyl-cycloprop-1 -yl, 1 -(morpholin-4-yl)methylcycloprop-1 -yl,

10 irazzs-2-hydroxymethyl-cycloprop-1 -yl, 1 -(hydroxymethyl)-cyclobut-1 -yl,

1- (2-hydroxyacetyl)azetidin-3-yl, (l-teri-butyloxycarbonyl)-3-hydroxyazetidin-3-yl,

3- hydroxyoxetan-3-yl, 3-(hydroxy(Ci-C3)alkyl)oxetan-3-yl, 3-aminooxetan-3-yl,

3-hydroxythietan-3-yl, 4-aminopiperidin-l-yl, morpholin-4-yl(C2-C3)alkoxy, [4-7V-(Ci-C3)alkylpiperazin-l-yl](Ci-C3)alkyl, morpholin-4-yl-(Ci-C2)alkyl, [l,2,3]triazol15 2-yl, 3-[hydroxy(C2-C3)alkyl]-2-oxo-imidazolidin-l-yl, (7s,3r)-(l-hydroxy 3-(hydroxymethyl)cyclobutyl)methyl, (4-hydroxypiperidinyl)methyl or (4-aminopiperidinyl)methyl;

R^1B represents 3-hydroxyoxetan-3-yl, 3-hydroxythietan-3-yl,

3-(hydroxy(Ci-C3)alkyl)oxetan-3-yl, hydroxy(Ci-C3)alkyl, 1,2-dihydroxyethyl,

20 amino(Ci-C3)alkyl, (dimethylamino)methyl, methylsulfonamidomethyl,

1 -aminocyclopropyl, 1 -hydroxymethyl-cycloprop-1 -yl, 1 -(carbamoyloxy )methylcycloprop-1 -yl, 1 -(((dimethylglycyl)oxy)methyl)cycloprop-1 -yl,

1 -((phosphonooxy)methyl)-cycloprop-1 -yl,

1 -((((phosphonooxy)methoxy)carbonyl)oxymethyl)cycloprop-1 -yl,

25 1 -((((phosphonooxy)methoxy)carbonyl)amino)-cycloprop-1 -yl, irazzs-2-hydroxymethylcycloprop-1 -yl, 1 -fluoro-2-hydroxymethyl-cycloprop-1 -yl, 2-fluoro-2-hydroxymethylcycloprop- 1 -yl, 1 -methyl-2-hydroxymethyl-cycloprop-1 -yl, 2-hydroxymethyl-

2- methylcycloprop-l-yl, (lR*,2S'*,3s*)-l,2-6zs-(hydroxymethyl)-cycloprop-3-yl,

30 3-yl, l-(2-hydroxyacetyl)-azetidin-3-yl, /ra/7.s-(cz.s-3,4-dihydiOxy)-cyclopent-l-yl,

3 -hydroxymethyl-bicyclo[ 1,1,1 ]pentan-1 -yl, 4-hydroxy-tetrahyd ro-2//-pyran-4-yl,

5-ammo-tetrahydiO-2//-pyran-2-yl, 3-hydroxyoxetan-3-ylmethyl, 1-cyclobutyl-

2- hydroxyethyl or l-(oxetan-3-yl)-azetidin-3-yl; and

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2015226250 05 Nov 2018

R^1C represents 1-aminocyclopropyl or hydroxy(Ci-C3)alkyl;

or a salt of this compound.

2. A compound of formula I according to claim 1, which is also a compound of formula Ip wherein

5 R¹ represents the group M;

M is one of the groups M^A and M^B represented below

R^1A _R3A

M^A M^B wherein A represents a bond, CH=CH or C=C;

U represents N or CH;

V represents N or CH;

10 R^1A represents H or halogen;

R^2A represents H, (Ci-C3)alkoxy or halogen;

R^3A represents H, (Ci-C3)alkoxy, hydroxy(C2-C4)alkoxy, (Ci-C3)alkoxy(Ci-C3)alkoxy, (Ci-C3)thioalkoxy, trifluoromethoxy, amino, hydroxy(Ci-C₄)alkyl, (C i -C3)alkoxy(C i -C₄)alkyl, 3 -hydroxy-3 -methylbut-1 -yn-1 -yl, 2-hydroxyacetamido,

15 (carbamoyloxy)methyl, 1-hydroxymethyl-cycloprop-1-yl, 1-aminomethyl-cycloprop-1-yl,

- 173 2015226250 05 Nov 2018

1 -(carbamoyloxy)methyl-cycloprop-1 -yl, 1 -(morpholin-4-yl)methylcycloprop-1 -yl, irazzs-2-hydroxymethyl-cycloprop-l-yl, 1,2-dihydroxyethyl, 3-hydroxyoxetan-3-yl, 3-(hydroxy(Ci-C3)alkyl)oxetan-3-yl, 3-aminooxetan-3-yl, 3-hydroxythietan-3-yl, morpholin-4-yl(C2-C3)alkoxy, [4-7V-(C i -C3)alkylpiperazin-1 -yl] (C i -C3)alkyl, morpholin5 4-yl-(Ci-C2)alkyl, [l,2,3]triazol-2-yl or 3-[hydroxy(C2-C3)alkyl]-2-oxo-imidazolidin-l-yl;

and

R^1B represents 3-hydroxyoxetan-3-yl, 3-hydroxythietan-3-yl,

3-(hydroxy(Ci-C3)alkyl)oxetan-3-yl, hydroxy(Ci-C3)alkyl, 1,2-dihydroxyethyl, amino(Ci-C3)alkyl, 1-hydroxymethyl-cycloprop-1-yl, irazzs-2-hydroxymethyl-cycloprop10 1-yl, irazzs-(czs-3,4-dihydroxy)-cyclopent-l-yl or 3-hydroxymethylbicyclo[1,1,1 ]pentan1-yi;

or a salt of this compound.

3. A compound of formula I according to claim 1, which is a compound of formula Ice wherein

15 R¹ represents the group M;

- 174 2015226250 05 Nov 2018

M is one of the groups M^A, M^B and M^c represented below

R^1A

R^1B

M^B wherein A represents a bond, CH=CH or C=C;

U represents CH orN;

V represents CH orN;

5 W represents CH orN;

R^1A represents H or halogen;

R^2A represents H, (Ci-C3)alkoxy or halogen;

R^3A represents H, halogen, (Ci-C3)alkoxy, hydroxy(C2-C4)alkoxy, dihydroxy(C3-C4)alkoxy, (C i -C3)alkoxy(C 1 -C3)alkoxy, tri fluoromethyl,

10 hydroxy(Ci-C4)alkyl,

1,2-dihydroxyethyl,

1 -hydroxy-2,2-difluoroethyl, (Ci-C₃)alkoxy(Ci-C₄)alkyl,

2-hydroxy-1 -oxoethyl, [(C i -C4)alkoxy] carbonyl, methylsulfonamidomethyl,

3-hydroxy-3 -methylbut-1 -yn-1 -yl, 2-hydroxyacetamido, (carbamoyloxy)methyl,

1 -aminocyclopropyl,

1 -hydroxymethyl-cycloprop-1 -yl, l-(((dimethylglycyl)oxy)methyl)-cyclopropyl,

1 -aminomethyl-cycloprop-1 -yl,

15 1 -(carbamoyloxy)methyl-cycloprop-1 -yl,

1 -(morpholin-4-yl)methyl-cycloprop-1 -yl, trans-2 -hydroxymethyl-cycloprop-1 -yl, 1 -(hydroxymethyl)-cyclobut-1 -yl, l-(2-hydroxyacetyl)azetidin-3-yl, (l-teri-butyloxycarbonyl)-3-hydroxyazetidin-3-yl,

3- hydroxyoxetan-3-yl, 3-(hydroxy(Ci-C3)alkyl)oxetan-3-yl, 3-aminooxetan-3-yl,

4- aminopiperidin-l-yl, [4-7V-(Ci-C3)alkylpiperazin-l-yl](Ci-C3)alkyl, morpholin-4-yl-

20 (Ci-C2)alkyl, 3-[hydroxy(C2-C3)alkyl]-2-oxo-imidazolidin-l-yl, (ls,3r)-(\-hydroxy- 175 2015226250 05 Nov 2018

3-(hydroxymethyl)cyclobutyl)methyl, (4-hydroxypiperidinyl)methyl or (4-aminopiperidinyl)methyl; and

R^1B represents 3-hydroxyoxetan-3-yl, hydroxy(Ci-C3)alkyl, 1,2-dihydroxyethyl, amino(Ci-C3)alkyl, (dimethylamino)methyl, methylsulfonamidomethyl,

5 1-aminocyclopropyl, 1-hydroxymethyl-cycloprop-l-yl, 1 -(carbamoyloxy )methylcycloprop-1 -yl, 1 -(((dimethylglycyl)oxy)methyl)cycloprop-1 -yl,

1 -((phosphonooxy)methyl)-cycloprop-1 -yl,

1 -((((phosphonooxy)methoxy)carbonyl)oxymethyl)-cycloprop-1 -yl,

1 -((((phosphonooxy)methoxy)carbonyl)amino)-cycloprop-1 -yl, irans-2-hydroxymethyl10 cycloprop-1-yl, l-fluoro-2-hydroxymethyl-cycloprop-l-yl, 2-fluoro-2-hydroxymethylcycloprop-1 -yl, 1 -methyl-2-hydroxymethyl-cycloprop-1 -yl, 2-hydroxymethyl-

2- methylcycloprop-l-yl, (lR*,2S'*,3s*)-l,2-

6zs-(hydroxymethyl)-cycloprop-3-yl, l-(hydroxymethyl)cyclobut-l-yl, 3-amino-oxetan-3-yl, 3-(hydroxy(Ci-C3)alkyl)oxetan-

3- yl, l-(2-hydroxy-acetyl)azetidin-3-yl, /ra/7.s-(cz.s-3,4-dihydiOxy)-cyclopent-l-yl,

15 3-hydroxymethylbicyclo[l,l,l]pentan-l-yl, 4-hydroxy-tetrahydro-2//-pyran-4-yl, 5-aminotetrahydro-2//-pyran-2-yl, 3-hydroxyoxetan-3-ylmethyl, l-cyclobutyl-2-hydroxyethyl or 1 -(oxetan-3-yl)-azetidin-3 -yl;

R^1C represents 1-aminocyclopropyl or hydroxy(Ci-C3)alkyl;

or a salt of this compound.

20 4. A compound of formula I according to any one of claims 1 to 3, wherein R¹ represents the group M^A;

or a salt of this compound.

5. A compound of formula I according to claim 4, wherein A represents a bond;

or a salt of this compound.

25 6. A compound of formula I according to claim 4, wherein A represents C=C;

or a salt of this compound.

7. A compound of formula I according to claim 6, wherein U represents CH, V represents

CH, R^1A represents H or fluorine, R^2A represents H or fluorine and R^3A represents hydroxy(C2-C4)alkoxy, hydroxy(Ci-C4)alkyl, 1,2-dihydroxyethyl, l-hydroxy-2,2- 176 2015226250 05 Nov 2018 difluoroethyl, methylsulfonamidomethyl, 2-hydroxyacetamido, (carbamoyloxy)methyl, 1 -aminocyclopropyl, 1 -hydroxymethyl-cycloprop-1 -yl, 1 -(carbamoyloxy )methylcycloprop-1 -yl, irazzs-2-hydroxymethyl-cycloprop-1 -yl, 1 -(hydroxymethyl)-cyclobut-1 -yl, 3-hydroxyoxetan-3-yl, morpholin-4-ylmethyl or (4-hydroxypiperidinyl)methyl;

5 or a salt of this compound.

8. A compound of formula I according to any one of claims 1 to 3, wherein R¹ represents the group M^B;

or a salt of this compound.

9. A compound of formula I according to claim 8, wherein R^1B represents

10 amino(Ci-C3)alkyl,

1 -aminocyclopropyl,

1 -hydroxymethyl-cycloprop-1 -yl, trans-2 -hydroxymethyl-cycloprop-1 -yl,

2-fluoro-2-hydroxymethyl-cycloprop-1 -yl,

2-hydroxymethyl-2-methylcycloprop-l-yl,

Zrazzs-(czs-3,4-dihydroxy)-cyclopent-l-yl,

1 -fluoro-2-hydroxymethyl-cycloprop-1 -yl,

1 -methyl-2-hydroxymethyl-cycloprop-1 -yl, l-(2-hydroxyacetyl)-azetidin-3-yl,

3-hydroxymethylbicyclo [1,1,1 Jpentan-1 -yl,

15 5-ammo-tetrahydro-2//-pyran-2-yl or l-(oxetan-3-yl)-azetidin-3-yl;

or a salt this compound.

10. A compound of formula I according to any one of claims 1 to 3, wherein R¹ represents the group M^c;

or a salt of this compound.

20

11. A compound of formula I according to claim 1, which is selected from the following:

- (7?)-4-(6-(2-fluoro-4-methoxyphenyl)-3-oxo-17/-pyrrolo[l,2-c]imidazol-2(377)-yl)-

TV-hy droxy-2 -methy 1-2 -(methylsulfonyl)butanamide;

- (/?)-A'-hyd roxy-4-(6-((4-(3 -hydroxyoxetan-3 -yl)phenyl)ethynyl)-3 -oxo17/-pyrrolo[l,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

25 - (7?)-7V-hydroxy-4-(6-((4-(hydroxymethyl)phenyl)ethynyl)-3-oxo17/-pyrrolo[l,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-7V-hydroxy-4-(6-((3-hydroxyoxetan-3-yl)buta-1,3-diyn-l-yl)-3-oxo-

17/-pyrrolo[l,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- 177 2015226250 05 Nov 2018

- (R)-7V-hydroxy-4-(6-((4-((7R,2R)-2-(hydroxymethyl)cyclopropyl)phenyl)ethynyl)-3-oxol//-pyrrolo[l ,2-c]imidazol-2(3//)-yl)-2-mcthyl-2-(mcthylsulfbnyl)butanamidc;

- (R)-7V-hydroxy-4-(6-((4-((7S',2S)-2-(hydroxymethyl)cyclopropyl)phenyl)ethynyl)-3-oxol//-pyrrolo[l ,2-c]imidazol-2(3//)-yl)-2-mcthyl-2-(mcthylsulfbnyl)butanamidc;

5 - (R)-7V-hydroxy-4-(6-((4-(l -(hydroxymethyl)cyclopropyl)phenyl)ethynyl)-3-oxol//-pyrrolo[l ,2-c]imidazol-2(3//)-yl)-2-mcthyl-2-(mcthylsulfbnyl)butanamidc;

- (R)-4-(6-((4-(l-(aminomethyl)cyclopropyl)phenyl)ethynyl)-3-oxo-

I //-pyrrol o[ 1,2-c]imidazol-2(3//)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl) butanamide;

- (7?)-7V-hydroxy-4-(6-((4-(l-hydroxy-2-methylpropan-2-yl)phenyl)ethynyl)-3-oxo-

10 I //-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-7V-hydroxy-4-(6-((4-(2-hydroxypropan-2-yl)phenyl)ethynyl)-3-oxol//-pyrrolo[l ,2-c]imidazol-2(3//)-yl)-2-mcthyl-2-(mcthylsulfbnyl)butanamidc;

- (R)-4-(6-((S)-5,6-dihydroxyhexa-l,3-diyn-l-yl)-3-oxo-17/-pyrrolo[l,2-c]imidazol2(3H)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

15 - (R)-7V-hydroxy-4-(6-(5-((7S',2S)-2-(hydroxymethyl)cyclopropyl)penta-l,3-diyn-l-yl)3-oxo- I//-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-2-mcthyl-2-(mcthylsulfbnyl)butanamidc;

- (7?)-7V-hydroxy-4-(6-((4-((7?)-1 -hydroxyethyl)phenyl)ethynyl)-3-oxo-

I//-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-2-mcthyl-2-(mcthylsulfbnyl)butanamidc;

- (R)-7V-hydroxy-4-(6-((4-((S)-1 -hydroxyethyl)phenyl)ethynyl)-3-oxo-

20 I //-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (/?)-/V-hyd roxy-4-(6-(( 1 -(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1 -y 1)-3 -oxol//-pyrrolo[l ,2-c]imidazol-2(3//)-yl)-2-mcthyl-2-(mcthylsulfbnyl)butanamidc;

- (7?)-7V-hydroxy-4-(6-((4-(2-hydroxyethyl)phenyl)ethynyl)-3-oxo- l//-pyrrolo[l ,2-c]imidazol-2(3//)-yl)-2-mcthyl-2-(mcthylsulfbnyl)butanamidc;

25 - (R)-4-(6-((4-((7?)-l,2-dihydroxyethyl)phenyl)ethynyl)-3-oxo-17/-pyrrolo[l,2-c]imidazol2(3H)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (R)-4-(6-((4-((S)-l,2-dihydroxyethyl)phenyl)ethynyl)-3-oxo-17/-pyrrolo[l,2-c]imidazol2(3//)-yl)-/V-hydroxy-2-mcthyl-2-(mcthylsulfbnyl)butanamidc;

- (R)-4-(6-((2-fluoro-4-(l-(hydroxymethyl)cyclopropyl)phenyl)ethynyl)-3-oxo-

30 I //-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (R)-7V-hydroxy-4-(6-((4-(3-(2-hydroxyethyl)-2-oxoimidazolidin-l-yl)phenyl)ethynyl)3-oxo-17/-pyrrolo[l,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

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2015226250 05 Nov 2018

- (R)-4-(6-((3-fluoro-4-(2-hydroxyacetamido)phenyl)ethynyl)-3-oxo17/-pyrrolo[l,2-c]imidazol-2(3//)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (R)-7V-hydroxy-4-(6-((4-(2-hydroxyethoxy)phenyl)ethynyl)-3-oxo- ///-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfbnyl)butanamide;

5 - (R)-7V-hydroxy-4-(6-((6-(l-(hydroxymethyl)cyclopropyl)pyridin-3-yl)ethynyl)-3-oxoI//-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfbnyl)butanamide;

- (R)-7V-hydroxy-4-(6-((5-(l-(hydroxymethyl)cyclopropyl)pyridin-2-yl)ethynyl)-3-oxo-

I//-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfbnyl)butanamide;

- (R)-7V-hydroxy-2-methyl-2-(methylsulfonyl)-

10 4-(6-((4-(moipholinomethyl)phenyl)ethynyl)-3-oxo-l//-pyrrolo[l,2-c]imidazol2 (3 //)-yl )bu tanami d c;

- (R)-7V-hydroxy-2-methyl-2-(methylsulfonyl)-

4-(6-((4-(l-(morpholinomethyl)cyclopropyl)phenyl)ethynyl)-3-oxo-

17/-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)butanamide;

15 - (R)-7V-hydroxy-4-(6-(((7R,2R)-2-(hydroxymethyl)cyclopropyl)buta-l,3-diyn-l-yl)-3-oxoI//-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfbnyl)butanamide;

- (R)-4-(6-(2-fluoro-3-methoxyphenyl)-3-oxo-17/-pyrrolo[l,2-c]imidazol-2(3//)-yl)-

A'-h yd rox y-2 -methy 1-2 -(methylsulfonyl)butanamide;

- (R)-(E)-7V-hydroxy-4-(6-(4-(hydroxymethyl)styryl)-3-oxo-1 //-pyrrolo[ 1,2-c]imidazol-

20 2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (R)-4-(6-(5-amino-5-methylhexa-1,3-diyn-1 -yl)-3-oxo-1 //-pyrrol o [ 1,2-c]imidazol2(3//)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (R)-4-((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-3-oxo-

2,3-dihydro-l//-pyrrolo[ 1,2-c]imidazol-6-yl)ethynyl)benzyl carbamate;

25 - (R)-4-(6-(((l S,3R,4S)-3,4-dihydroxycyclopentyl)buta- 1,3-diyn-l-yl)-3-oxoI//-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-A'-hydroxy-2-methyl-2-(methylsulfbnyl)butanamide;

- (R)-(l-(4-((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-3-oxo-

2.3- dihydro-l//-pyrrolo[ 1,2-c]imidazol-6-yl)ethynyl)phenyl)cyclopropyl)methyl carbamate;

30 - (Λ)-(1 -((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-3-oxo-

2.3- dihydro-1 //-pyrrol o [ 1,2-c]imidazol-6-yl)buta-l ,3-diyn- l-yl)cyclopropyl)methyl carbamate;

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2015226250 05 Nov 2018

- (/?)-/V-hydroxy-4-(6-(((//?,2/?)-2-(hydroxymethyl)-l-methylcyclopropyl)buta-l,3-diynl-yl)-3-oxo-lA-pyrrolo[l,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

2.3- dihydro-lA-pyrrolo[l,2-c]imidazol-6-yl)ethynyl)phenyl)cyclopropyl)methyl

5 dimethylglycinate;

- (7?)-4-(6-((1 -aminocyclopropyl)buta-1,3 -diyn-1 -y 1)-3 -oxo-I //-pyrrol o [ 1,2-c] imidazol2(3A)-yl)-A-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (R)-4-(6-((3-aminooxetan-3-yl)buta-l,3-diyn-l-yl)-3-oxo-l//-pyrrolo[l,2-c]imidazol2(3A)-yl)-A-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

10 - (R)-7V-hydroxy-4-(6-((4-(l-(hydroxymethyl)cyclobutyl)phenyl)ethynyl)-3-oxo///-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfbnyl)butanamide;

- (R)-4-(6-(2-fluoro-4-(2-hydroxyethoxy)phenyl)-3-oxo-I //-pyrrolof 1,2-c]imidazol2(3//)-yl)-/V-hydroxy-2-methyl-2-(methylsulfbnyl)butanamide;

- (Λ)-4-(6-(((2Λ,3S)-2,3-bis(hydroxymethyl)cyclopropyl)buta-l,3-diyn-l-yl)-3-oxo-

15 I //-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-A-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (R)-4-(6-(4-((R)-2,3-dihydroxypropoxy)-2-fluorophenyl)-3-oxo- l//-pyrrolo[l ,2-c]imidazol-2(3A)-yl)-A-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (R)-4-(6-((4-(l,1 -difluoro-2-hydroxyethyl)phenyl)ethynyl)-3-oxol//-pyrrolo[l,2-c]imidazol-2(3//)-yl)-A-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

20 - (R)-A-hydroxy-4-(6-((4-(2-hydroxyacetyl)phenyl)ethynyl)-3-oxol//-pyrrolo[l ,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfbnyl)butanamide;

- (R)-4-(6-(5-(dimethylamino)penta-l,3-diyn-l-yl)-3-oxo-l//-pyrrolo[l,2-c]imidazol2(3//)-yl)-/V-hydroxy-2-methyl-2-(methylsulfbnyl)butanamide;

- methyl (R)-3 -fluoro-4-(2-(4-(hydroxyamino)-3 -methyl-3 -(methylsulfonyl)-4-oxobutyl)-

25 3-oxo-2,3-dihydiO-l//-pyriOlo[l,2-c]imidazol-6-yl)benzoate;

- (/?)-4-(6-(4-chloro-2-fluorophcnyl)-3-oxo-l//-pyrrolo[l ,2-c]imidazol-2(3//)-yl)-

A- hy d rox y-2 -methy 1-2 -(methylsulfonyl)butanamide;

- (/?)-4-(6-(2-chloro-4-ethoxyphenyl)-3-oxo-l//-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-

A'- hy d rox y-2 -methy 1-2 -(methylsulfonyl)butanamide;

30 - (R)-(l-((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-3-oxo-

2.3- dihydro-l//-pyrrolo[l ,2-c]imidazol-6-yl)buta-l ,3-diyn-l-yl)cyclopropyl)methyl dimethylglycinate;

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2015226250 05 Nov 2018

- (R)-(l-((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-3-oxo-

2,3-dihydro-1 //-pyrrol o [ 1,2-c]imidazol-6-yl)buta-l ,3-diyn- l-yl)cyclopropyl)methyl dihydrogen phosphate;

- (R)-4-(6-(2-chloro-4-methoxyphenyl)-3-oxo-l//-pyrrolo[l,2-c]imidazol-2(3//)-yl)-

5 7V-hy droxy-2 -methy 1-2 -(methylsulfonyl)butanamide;

- (R)-4-(6-(2-fluoro-4-(trifluoromethyl)phenyl)-3-oxo-l//-pyrrolo[ 1,2-c]imidazol2(3//)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-7V-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(2,3,4-trifluorophenyl)l//-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)butanamide;

10 - (R)-4-(6-(2,3-difluoro-4-methoxyphenyl)-3-oxo-l//-pyrrolo[l,2-c]imidazol-2(3//)-yl)·

7V-hy droxy-2 -methy 1-2 -(methylsulfonyl)butanamide;

- (/?)-A'-hydroxy-4-(6-(( 1 -(hydroxymethyl)cyclobutyl)buta-1,3-diyn-1 -y 1)-3-oxol//-pyrrolo[l,2-c]imidazol-2(3//)-yl)2-methyl-2-(methylsulfonyl)butanamide;

- ((7?)-7V-hydroxy-4-(6-((3-(hydroxymethyl)oxetan-3-yl)buta-l,3-diyn-l-yl)-3-oxo-

15 1 //-pyrrol o[ 1,2-c]imidazol-2(3//)-yl)-2-mcthyl-2-(mcthylsulfbnyl)butanamidc;

- (7?)-/V-hydroxy-2-methyl-4-(6-(5-(methylsulfonamido)penta-l,3-diyn-l-yl)-3-oxol//-pyrrolo[l,2-c]imidazol-2(3//)-yl)2-(niethylsulfonyl)butanamide;

- teri-butyl (7?)-3-hydroxy-3-(4-((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)4-oxobutyl)-3-oxo-2,3-dihydro- l//-pyrrolo[ 1,2-c]imidazol-6-yl)ethynyl)phenyl)azetidine-

20 1-carboxylate;

- (2R)-4-(6-(5-cyclobutyl-6-hydroxyhexa-l,3-diyn-l-yl)-3-oxo-l//-pyrrolo[l,2-c]imidazol2(3//)-yl)-/V-hydiOxy-2-methyl-2-(methylsulfbnyl)butanamide;

- (R)-7V-hydroxy-4-(6-(((7R,2S)-2-(hydroxymethyl)-2-methylcyclopropyl)buta-1,3-diynl-yl)-3-oxo-l//-pyrrolo[l,2-c]imidazol-2(3//)-yl)2-methyl-2-(methylsulfonyl)butanamide;

25 - (7?)-/V-hydroxy-4-(6-((l-(2-hydroxyacetyl)azetidin-3-yl)buta-1,3-diyn-l-yl)-3-oxol//-pyrrolo[l,2-c]imidazol-2(3//)-yl)2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-7V-hydroxy-4-(6-(5-(3-hydroxyoxetan-3-yl)penta-l,3-diyn-l-yl)-3-oxol//-pyrrolo[l,2-c]imidazol-2(3//)-yl)2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-/V-hydroxy-4-(6-((4-hydroxytetrahydro-2Z/-pyran-4-yl)buta-1,3-diyn-1 -yl)-3-oxo-

30 l//-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-2-mcthyl-2-(methylsulfbnyl)butanamide;

- (^)-4-(6-(((25,5/?)-5-aminotetrahydro-2//-pyran-2-yl)buta-1,3-diyn-1 -y 1)-3-oxol//-pyrrolo[l ,2-c]imidazol-2(3//)-yl)-/V-hydiOxy-2-methyl-2-(methylsulfbnyl)butanamide;

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- (7?)-4-(6-(((7R ,2R)-1 -fluoro-2-(hydroxymethyl)cyclopropyl)buta-1,3 -diyn-1 -y 1)-3 -oxo177-pyrrolo[l,2-c]imidazol-2(377)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-4-(6-(((75,2S)-l-fluoro-2-(hydroxymethyl)cyclopropyl)buta-l,3-diyn-l-yl)-3-oxo177-pyrrolo[l,2-c]imidazol-2(377)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

5 - ¢5)-4-(6-((5-(1 -aminocyclopropyl)thiophen-2-yl)ethynyl)-3-oxo177-pyrrolo[l,2-c]imidazol-2(377)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-4-(6-((4-(3-aminooxetan-3-yl)phenyl)ethynyl)-3-oxo-177-pyrrolo[l,2-c]imidazol2(377)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (5)-7V-hydroxy-4-(6-((4-(3-(hydroxymethyl)oxetan-3-yl)phenyl)ethynyl)-3-oxo-

10 177-pyrrolo[ 1,2-c]imidazol-2(377)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (5)-7V-hydroxy-4-(6-((4-(2-hydroxyacetamido)phenyl)ethynyl)-3-oxo177-pyrrolo[l,2-c]imidazol-2(377)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (5)-4-(6-((4-( 1 -aminocyclopropyl)phenyl)ethynyl)-3 -oxo- 177-pyrrolo [ 1,2-c] imidazol2(377)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

15 - (5)-7V-hydroxy-4-(6-(5-((7s,37?)-l-hydroxy-3-(hydroxymethyl)cyclobutyl)penta-l,3-diyn1 -yl)-3-oxo- 177-pyrrolo[ 1,2-c]imidazol-2(377)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

- (phosphonooxy)methyl (7?)-(l-((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-

4-oxobutyl)-3-oxo-2,3-dihydro-177-pyrrolo[ 1,2-c]imidazol-6-yl)buta-1,3-diyn1 -yl)cyclopropyl)carbamate;

20 - (7?)-(l-((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-3-oxo-

2,3-dihydro-177-pyrrolo[ 1,2-c]imidazol-6-yl)buta-1,3-diyn-l -yl)cyclopropyl)methyl ((phosphonooxy)methyl) carbonate;

- (7?)-7V-hydroxy-4-(6-((2-(2-hydroxypropan-2-yl)thiazol-5-yl)ethynyl)-3-oxo177-pyrrolo[l,2-c]imidazol-2(377)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

25 - (7?)-4-(6-((4-((4-aminopiperidin-l-yl)methyl)phenyl)ethynyl)-3-oxo177-pyrrolo[l,2-c]imidazol-2(377)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-4-(6-(((77?,27?)-2-fluoro-2-(hydroxymethyl)cyclopropyl)buta-l,3-diyn-l-yl)-3-oxo-

177-pyrrolo[l,2-c]imidazol-2(377)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- ¢5)-4-(6-(((75,25)-2-fluoro-2-(hydroxymethyl)cyclopropyl)buta-l,3-diyn-l-yl)-3-oxo-

30 177-pyrrolo[ 1,2-c]imidazol-2(377)-yl)-7V-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (7?)-7V-hydroxy-4-(6-((4-((4-hydroxypiperidin-1 -yl)methyl)phenyl)ethynyl)-3-oxo177-pyrrolo[l,2-c]imidazol-2(377)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

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- (R)-4-(6-((4-(4-aminopiperidin-1 -yl)phenyl)ethynyl)-3 -oxo- I //-pyrrolo[ 1,2-c] imidazol2(3//)-yl)-A-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

- (/?)-A-hydroxy-2-methyl-4-(6-((4-(methylsulfonamidomethyl)phenyl)ethynyl)-3-oxo17/-pyrrolo[l,2-c]imidazol-2(3//)-yl)-2-(methylsulfonyl)butanamide;

5 - (/?)-A-hydroxy-2-methyl-2-(methylsulfonyl)-4-(6-((l-(oxetan-3-yl)azetidin-3-yl)buta-

1,3-diyn-l-yl)-3-oxo-l//-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)butanamide;

- (R)-7V-hydroxy-4-(6-(4-(3-hydroxyoxetan-3-yl)phenyl)-3-oxo-17/-pyrrolo[l,2-c]imidazol2(3//)-yl)-2-mcthyl-2-(mcthylsulfbnyl)butanamidc;

- (/?)-4-(6-((4-(2-ethoxypropan-2-yl)phenyl)ethynyl)-3-oxo-l//-pyrrolo[l,2-c]imidazol-

10 2(3//)-yl )-A'-hydroxy-2-methyl-2-(methylsulfbnyl )butanamide;

- (/?)-4-(6-((2-fluoro-4-(hydroxymethyl)phenyl)ethynyl)-3-oxo-l//-pyrrolo[l,2-c]imidazol2(3//)-yl)-A'-hydroxy-2-methyl-2-(methylsulfbnyl)butanamide;

- (/?)-A'-hyd roxy-4-(6-(4-(3 -hydroxy-3 -methylbut-1 -yn-1 -yl)phenyl)-3 -oxo- l//-pyrrolo[l ,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfbnyl)butanamide;

15 - (/?)-A-hydroxy-4-(6-(5-hydroxy-5-methylhexa-l,3-diyn-l-yl)-3-oxol//-pyrrolo[l ,2-c]imidazol-2(3//)-yl)-2-methyl-2-(methylsulfbnyl)butanamide;

- (/?)-A-hydroxy-2-methyl-4-(6-((4-((4-methylpiperazin-1 -yl)methyl)phenyl)ethynyl)-

3-oxo-l//-pyrrolo[ 1,2-c]imidazol-2(3//)-yl)-2-(me4hylsulfbnyl)butanamide;

- (/?)-A'-hydroxy-4-(6-(4-(2-hydroxyethoxy)phenyl)-3-oxo-l//-pyrrolo[l ,2-c]imidazol-

20 2(3//)-yl)-2-mcthyl-2-(mcthylsulfbnyl)butanamidc;

- (7?)-A-hydroxy-4-(6-(4-(2-methoxyethoxy)phenyl)-3-oxo- I //-pyrrolo[ 1,2-c]imidazol-

2(3//)-yl)-2-mcthyl-2-(mcthylsulfbnyl)butanamidc;

- (/?)-4-(6-(2-fluoro-4-methylphenyl)-3-oxo-177-pyrrolo[l,2-c]imidazol-2(3//)-yl)-

A-hyd rox y-2 -methy 1-2 -(methylsulfonyl)butanamide;

25 - (/?)-4-(6-(3-fluoro-4-isopropoxyphenyl)-3-oxo-l//-pyrrolo[l,2-c]imidazol-2(3//)-yl)A-hyd rox y-2 -methy 1-2 -(methylsulfonyl)butanamide;

or a salt of this compound.

12. A method of treating a patient with a Gram-negative bacterial infection comprising administering to the patient an effective amount of a compound of formula I as defined in 30 any one of claims 1 to 11.

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13. A pharmaceutical composition containing, as active ingredient, a compound of formula I as defined in any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.

14. A compound of formula I as defined in any one of claims 1 to 11, or a

5 pharmaceutically acceptable salt thereof, when used for the prevention or treatment of a Gram-negative bacterial infection.

15. The use of a compound of formula I as defined in any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a Gram-negative bacterial infection.